The present invention relates to substituted benzene compounds, process for their preparation, and herbicidal and defoliant compositions containing them.
Use of uracils as herbicides has previously been reported. For example, U.S. Pat. Nos. 4,859,229 and 4,746,352 describe 3-phenyl uracil derivatives as herbicides. However the phenyl ring in the described compounds carry only four substituents. U.S. Pat. No. 4,927,451 describes herbicidal compounds carrying five substituents on the phenyl ring with a dihydrouracil ring. EP patent 0705829 describes uracil herbicides carrying pentasubstituted phenyl ring with a carbon linked substiutent at position 2 of the phenyl ring. U.S. Pat. Nos. 5,346,881, 5,441,925, 5,169,431, 5,476,834, 5,602,077, and WO patents 97/08170, 08171, 12886 and 42188 describe uracil herbicides carrying a fused pentasubstituted phenyl ring where the 2 position of the phenyl ring is substituted either with a carbon, oxygen or nitrogen. U.S. Pat. No. 5,116,404 and JP patent 05025144 describe uracil compounds with a 3-phenyl group which may be pentasubstituted but none of these patents appears to make obvious the compounds of the present invention which carry a nitrogen linked substituent at position 2 of the phenyl ring alongwith substituents at positions 3, 4, and 6 and there appears to be no indication as to the criticality of the substitution pattern of the phenyl moiety in order to introduce the high herbicidal activity in combination with selectivity towards crops. Similarly use of pyrazole, tetrahydrophthalimide, triazolinone, tetrazolinone, and triazolidine derivatives as herbicides has been described before such as U.S. Pat. Nos. 5,281,571, 4,881,967, 5,084,085, WO patent 85/01939, and Japanese patent 1-121290 respectively. Pyridazinones, pyridyls, bicyclic hydantoins, phthalimides, pyrimidinones, pyrazinones, and pyridinones have also been described as herbicides such as WO patents 97/07104, 95/02580, 95/23509, EP patent 0786453, WO patents 97/06150, 97/11060, and 97/28127. However, despite the broad coverage of these patents, the general structure of the present invention has not been described.
This invention delineates a method for the control of undesired vegetation in a plantation crop by the application to the locus of the crop an effective amount of a compound described herein. The herbicidal and defoliant compounds of the present invention are described by the following general formula I or its salts: 
wherein
X is hydrogen, halogen, nitro, amino, NHR, N(R)2, amide, thioamide, cyano, alkylcarbonyl, alkoxycarbonyl, alkylsulfonamide, unsubstituted or substituted alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonylalkoxy, benzyloxy, aryloxy, or heteroaryloxy;
Y is hydrogen, halogen, or nitro;
W is hydrogen, OR, SR, NHR, N(R)2, CH2R, CH(R)2, or C(R)3, halogen, nitro, or cyano, where multiple R groups represent any possible combination of substituents described by R; R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, aryloxy, heteroaryloxy, alkylsulfonyl, benzyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, or heteroaryloxycarbonyl, where any of these groups may be unsubstituted or substituted with any of the functional groups represented by one or more of the following: halogen, cyano, nitro, amino, carboxyl, alkyl, haloalkyl, alkylsilyl, alkylcarbonyl, haloalkylcarbonyl, alkoxy, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, or cycloalkyl;
Q is a heterocycle, examples of which are as follows: 
xe2x80x83wherein
R1 is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, amino, alkoxyalkyl, acetyl, alkoxycarbonylamino, alkylcarbonylamino, or alkoxycarbonyl;
R2 is alkyl or haloalkyl;
R1 and R2 could combine to form a five- or six-membered heterocyclic ring;
R3 is hydrogen, halogen, nitro, amino, alkylamino, haloalkylamino, cyano, or amide;
R8 and R9 are independently oxygen, sulfur, or imino group;
Q6, Q7, and Q10 may optionally be unsaturated containing one or two double bonds in the 6-membered ring;
Z is amino, hydroxyl, thiol, formyl, carboxyl, cyano, alkylcarbonyl, arylcarbonyl, azido, or one of the following: 
wherein R4 is alkyl, alkenyl, alkynyl, amino, cycloalkyl, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, benzyl, aryl, heteroaryl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkylthiocarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, arylthio-carbonyl, aryl-thiocarbonyl, heteroaryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, alkoxycarbonylcarbonyl or arylcarbonylcarbonyl, where any of these groups may be unsubstituted or substituted with any of the functional groups represented by one or more of the following: halogen, cyano, nitro, amino, dialkylamino, hydroxyl, carboxyl, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcarbonyl, alkylcarbonyloxy, alkoxy, alkoxycarbonyl, alkylthio, alkylthiocarbonyl, alkoxythiocarbonyl alkylaminocarbonyl, arylaminocarbonyl, alkylsulfonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryl, arylcarbonyl, aryloxy, aryloxycarbonyl, arylthio, heteroaryl, heteroaryloxycarbonyl or methylenedioxy, wherein the alkyl moiety or aryl moiety may be substituted with halogen, cyano, nitro, alkyl, alkoxy, haloalkyl, haloalkoxy, alkoxycarbonyl, cycloalkyl, aryl, or heterocycloalkyl; and R5 is hydrogen or any one of the groups represented by R4; or R4 and R5 could combine to form a 4-8 membered heterocyclic ring; 
wherein R6 represents alkyl, haloalkyl, dialkylamino, unsubstituted or substituted aryl and heteroaryl; and R7 represents hydrogen, halogen or any of the groups represented by R6;
xe2x80x94OR4,
xe2x80x94SR4,
xe2x80x94CH2R10,
xe2x80x94CH(R10)2,
xe2x80x94C(R10)3, or
xe2x80x94CHxe2x95x90CHR10 
xe2x80x83wherein R10 is carboxyl, alkyl, alkenyl, alkynyl, amino, cycloalkyl, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, benzyl, aryl, heteroaryl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkylthiocarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, arylthio-carbonyl, aryl-thiocarbonyl, heteroaryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, alkoxycarbonylcarbonyl or arylcarbonylcarbonyl, where any of these groups may be unsubstituted or substituted with any of the functional groups represented by one or more of the following: halogen, cyano, nitro, amino, dialkylamino, hydroxyl, carboxyl, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcarbonyl, alkylcarbonyloxy, alkoxy, alkoxycarbonyl, alkylthio, alkylthiocarbonyl, alkoxythiocarbonyl alkylaminocarbonyl, arylaminocarbonyl, alkylsulfonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryl, arylcarbonyl, aryloxy, aryloxycarbonyl, arylthio, heteroaryl, heteroaryloxycarbonyl or methylenedioxy, wherein the alkyl moiety or aryl moiety may be substituted with halogen, cyano, nitro, alkyl, alkoxy, haloalkyl, haloalkoxy, alkoxycarbonyl, cycloalkyl, aryl, or heterocycloalkyl;
provided that (1) Z is not alkyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, alkenyl, haloalkenyl, amino, monoalkylamino, dialkylamino, alkoxyalkoxy or cyano, when Q is Q1 and R2 is haloalkyl,
(2) Z is not amino when Q is Q3, and
(3) Z is not hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, haloalkenyloxy, or xe2x80x94NR4R5, wherein R4 is alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, haloalkenyl, alkylsulfonyl, alkylcarbonyl, alkoxycarbonyl, or cycloalkylalkyl, and R5 is alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyll haloalkenyl, alkylcarbonyl, alkoxycarbonyl, or cycloalkylalkyl, when Q is Q14 or Q15.
In the above definitions, the term alkyl used either alone or in compound words such as haloalkyl indicates either straight chain or branched alkyls containing 1-8 carbon atoms. Alkenyl and alkynyl include straight chain or branched alkenes and alkynes respectively containing 2-8 carbon atoms. The term halogen either alone or in the compound words such as haloalkyl indicates fluorine, chlorine, bromine, or iodine. Further a haloalkyl is represented by an alkyl partially or fully substituted with halogen atoms which may be same or different. A cycloalkyl group implies a saturated or unsaturated carbocycle containing 3-8 carbon atoms. A heterocycloalkyl group is a cycloalkyl group carrying 1-4 heteroatoms which are represented by oxygen, nitrogen, or sulfur atoms. An aryl group signifies an aromatic carbocycle containing 4-10 carbon atoms, and may be phenyl or naphthyl. A heteroaryl group is an aromatic ring containing 1-4 heteroatoms which are represented by oxygen, nitrogen, or sulfur atoms, and may for example be furanyl, pyridyl, thienyl, pyrimidinyl, benzofuranyl, quinolyl, benzothienyl or quinoxalyl.
The compound of the formula I may form a salt with an acidic substance or a basic substance. The salt with an acidic substance may be an inorganic acid salt such as a hydrochloride, a hydrobromide, a phosphate, a sulfate or a nitrate. The salt with a basic substance may be a salt of an inorganic or organic base such as a sodium salt, a potassium salt, a calcium salt, a quarternary ammonium salt such as ammonium salt or a dimethylamine salt.
The compound of the formula I may exist as geometrical or optical isomers and the present invention includes all of these isomeric forms.
Preferred compounds for the reasons of ease of synthesis or greater herbicidal efficacy are represented by the formula I wherein
(1) Z is xe2x80x94NR4R5 or xe2x80x94CH2R10,
(2) X is halogen or cyano; Y is halogen; W is xe2x80x94OR; and R is alkyl, alkenyl, or alkynyl, where any of these groups may be unsubstituted or substituted with any of the functional groups represented by one or more of the following: halogen, cyano, nitro, amino, or carboxyl, or
(3) Q is Q1 or Q6; R1 is alkyl, amino or haloalkyl; R2 is haloalkyl; R3 is hydrogen; and R8 and R9 are independently oxygen, sulfur, or imino group,
Still more preferred compounds for the reasons of greater herbicidal efficacy are represented by formula I wherein X is halogen; Y is fluorine; W is OR; R is alkyl, alkenyl, or alkynyl, where any of these groups may be unsubstituted or substituted with halogen or cyano; Q is Q1 or Q6; R1 is alkyl, amino, or haloalkyl; R2 is haloalkyl; R3 is hydrogen; and R8 and R9 are independently oxygen, sulfur, or imino group; Z is xe2x80x94NR4R5; R4 is alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkylthiocarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, arylthio-carbonyl, aryl-thiocarbonyl, heteroaryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, alkoxycarbonylcarbonyl, arylcarbonylcarbonyl, where any of these groups may be unsubstituted or substituted with any of the functional groups represented by one or more of the following: halogen, cyano, nitro, amino, dialkylamino, hydroxyl, carboxyl, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcarbonyl, alkylcarbonyloxy, alkoxy, alkoxycarbonyl, alkylthio, alkylthiocarbonyl, alkoxythiocarbonyl alkylaminocarbonyl, arylaminocarbonyl, alkylsulfonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryl, arylcarbonyl, aryloxy, aryloxycarbonyl, arylthio, heteroaryl, heteroaryloxycarbonyl, or methylenedioxy, wherein the alkyl moiety or aryl moiety may be substituted with halogen, cyano, nitro, alkyl, alkoxy, haloalkyl, haloalkoxy, alkoxycarbonyl, cycloalkyl, aryl, or heterocycloalkyl; and R5 is hydrogen; or Z is xe2x80x94CH2R10; R10 is carboxyl, alkyl, alkenyl, or alkynyl, where any of these groups may be unsubstituted or substituted with any of the functional groups represented by one or more of the following: halogen, cyano, nitro, amino, dialkylamino, hydroxyl, carboxyl, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcarbonyl, alkylcarbonyloxy, alkoxy, alkoxycarbonyl, alkylthio, alkylthiocarbonyl, alkoxythiocarbonyl alkylaminocarbonyl, arylaminocarbonyl, alkylsulfonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryl, arylcarbonyl, aryloxy, aryloxycarbonyl, arylthio, heteroaryl, heteroaryloxycarbonyl, or methylenedioxy, wherein the alkyl moiety or aryl moiety may be substituted with halogen, cyano, nitro, alkyl, alkoxy, haloalkyl, haloalkoxy, alkoxycarbonyl, cycloalkyl, aryl, or heterocycloalkyl.
Certain intermediates of the present invention are novel. These are 3-(2-amino-4-chloro-6-fluoro-3-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione, 3-(2-amino-4-chloro-6-fluoro-3-methoxyphenyl)-1-amino-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione and represented by the following formulae (III-V): 
wherein X, Y, W and Q are the same as defined above; and M is nitro. 
wherein Xxe2x80x2 and Yxe2x80x2 are halogens; and R is the same as defined above.
The compounds described by the formula I can be prepared by the procedures as described herein. In general, the compounds described in this invention can be prepared by one of the two routes depending on whether the heterocyclic ring (e.g. uracil ring) is formed prior to or after the nitration at the 2 position of the phenyl ring in the final product.
As depicted in Scheme I, the starting materials for these preparations are the compounds represented by the formula VIc. These compounds can be prepared starting from the nitro compound VIa via the amine VIb by the procedures described in literature, for example U.S. Pat. No. 4,859,229 (1989). Nitration of VIc is typically carried out by its slow addition to a mixture of sulfuric acid and nitric acid in a ratio of 9:1. Typically 3-4 ml of the nitration mixture is used for 2-3 mmol of VI and the addition is carried out between 0 to xe2x88x9230xc2x0 C. followed by stirring at ambient temperature for 0.5-2 hr. Product (VII) is separated by addition of the solution to ice water and filtration of the precipitate. The product can also be extracted from aqueous layer into organic solvents such as ether or ethyl acetate and purified by crystallization or column chromatography. Alkylation of VII to VIII can be accomplished by treatment of VII with alkyl halide, haloalkyl halide, especially the respective chloride, bromide, or sulfate in the presence of a base such as potassium carbonate or sodium hydride in an inert solvent such as acetone, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, methyl ethyl ketone, or acetonitrile at a temperature range of 0 to 130xc2x0 C. VIII can be reduced to the amine (IX) under typical reduction conditions such as treatment with iron in acetic acid or ethanolic hydrochloric acid; or by hydrogenation using palladium on carbon or platinum oxide as catalyst. The product IX is purified by typical purification procedures of recrystallization or column chromatography.
The amine (IX) can be derivatized to yield a variety of products generally represented by the formula X. For example amides can be prepared by treatment of IX with alkyl or aryl acid halides, typically chlorides, or anhydrides in the presence of base in an inert solvent. Typically organic bases such as triethylamine, diisopropylethylamine, or pyridine can be used in inert solvents such as tetrahydrofuran, acetonitrile, or dioxane at a temperature range of ambient to reflux temperature for 2-24 hr. Pyridine can be used alone as solvent and base. Acylation catalysts such as dimethylaminopyridine (DMAP) can be added to facilitate the reaction. Typical work-up procedure includes removal of solvent followed by partitioning of the product between aqueous and organic solvents such as ether, ethyl acetate or methylene chloride. Depending upon the reactivity of the acid halide, the product typically consists of a monoamide, diamide, or a mixture of the two. These can be purified/resolved typically by column chromatography. Mono or dialkyl (amino) derivatives of IX can be prepared by its treatment with alkyl or haloalkyl halides in the presence of base such as potassium or sodium carbonate, or sodium hydride in an inert solvent such as tertahydrofuran or dimethylformamide at a temperature of ambient to 120xc2x0 C. for 2-24 hr. Mono or dicarbamoyl derivatives of IX can be prepared by its treatment with alkylhaloformates such as methyl or ethylchloroformate in the presence of base such as potassium or sodium carbonate in an inert solvent such as tertahydrofuran or dimethylformamide at a temperature of ambient to 120xc2x0 C. for 2-24 hr. Mono or di urea derivatives of IX can be prepared by its treatment with an alkyl or aryl isocyanate, for example methyl or ethyl isocayante, in the presence of a base such as triethylamine in an inert solvent such as toluene or tetrahydrofuran. Alternatively, IX is first converted into its isocyanate derivative by treatment with phosgene or triphosgene in toluene or tetrahydrofuran at reflux temperature for 2-6 hr. This isocyanate can, in turn, be treated with an alkyl or aryl amine such as methyl or ethyl amine in the presence of a base such as triethylamine in an inert solvent such as toluene or tetrahydrofuran at a temperature range of ambient to 130xc2x0 C. for 2-12 hr to furnish the corresponding urea. IX can be treated with an alkyl dihalide such as 1,4-diiodobutane in an inert solvent such as toluene or acetonitrile at reflux temperature in the presence of a base such as potassium or sodium carbonate to furnish the corresponding cyclized product such as a pyrrolidine derivative. IX can be treated with an aromatic or aliphatic aldehyde or ketone or its diethyl or dimethyl acetal derivative in an inert solvent such as toluene or methylene chloride to furnish the corresponding imino derivative. Alternatively, a monoacetyl derivative of IX can be treated with a dehydrochlorinating agent such as phosphorus pentachloride to furnish the corresponding iminochloride. 
The starting uracil derivative represented by formula XI in Scheme 2 can be prepared according to the procedure as described before. The compound XI is nitrated with concentrated nitric acid at 0xc2x0 C. to ambient temperature for 15xcx9c30 minutes. Product (XII) is obtained by addition of the product mixture to ice-water followed by filtration. 
The starting uracil derivative represented by formula XIII in Scheme 3 can be prepared according to the procedure as previously described. Compound XIII can be nitrated with nitric acid at 0xc2x0 C. for 15xcx9c30 minutes. Product (XIV) is obtained by addition of ice followed by filtration. 
The desired starting tetrazole derivatives represented by formula XV in Scheme 4 can be prepared according to the literature procedure of WO 85/01939. These compounds can be nitrated with nitric acid at ambient temperature or at 0xc2x0 C. for 15xcx9c30 minutes. Product (XVI) is isolated by addition of ice followed by extraction into an organic solvent such as ether or ethyl acetate and purified. XVII can be prepared by the reduction of XVI typically by catalytic hydrogenation in presence of catalysts such as palladium on carbon or by treatment with iron in acetic acid or in ethanolic hydrochloric acid. XVIII can be prepared by reacting XVII with a halide in presence of a base at 50 to 120xc2x0 C. for 1xcx9c5 hours. Further modification of XVIII to XIX is carried out according to the general procedures described for the preparation of X from IX (Scheme I). 
The starting triazolinone derivative represented by formula XX in Scheme 5 can be prepared according to the literature procedure of U.S. Pat. No. 4,980,480 (1990). The compound XX is nitrated with concentrated nitric acid at xe2x88x9215 to 0xc2x0 C. for 0.5-2 hr. Product (XXI) is obtained by addition of the product mixture to ice-water followed by filtration. 
The desired starting pyrazole derivatives represented by formula XXII in Scheme 6 can be prepared according to the literature procedure of U.S. Pat. No. 5,281,571 (1994). These compounds can be nitrated in sulfuric acid-nitric acid mixture (9:1) with a ratio of 3-4 ml of the nitrating solution to 3-4 mmol of XXII. The addition is carried out between xe2x88x9215 to xe2x88x9230xc2x0 C. followed by stirring at ambient temperature for 1-2 hr. Product (XXIII) is isolated by addition of water followed by extraction into an organic solvent such as ether or ethyl acetate and purified. XXIV can be prepared by the reduction of XXIII typically by catalytic hydrogenation in presence of catalysts such as palladium on carbon or by treatment with iron in acetic acid or in ethanolic hydrochloric acid. Further modification of XXIV to XXV is carried out according to the general procedures described for the preparation of X from IX (Scheme I). 
The desired starting tetrahydrophthalimide derivative represented by formula XXVI in Scheme 7 can be prepared according to the literature procedure of U.S. Pat. No. 4,484,941 (1984). The compound can be nitrated with nitric acid at 0xc2x0 C. to ambient temperature for half hour. The product (XXVII) is isolated by addition of ice followed by extraction into an organic solvent such as ether, ethyl acetate, or methylene chloride and purified. XXVIII can be prepared by the reduction of XXVII typically by catalytic hydrogenation in presence of catalysts such as palladium on carbon or by treatment with iron in acetic acid or in ethanolic hydrochloric acid. XXIX can be prepared by reacting XXVIII with (substituted)alkyl halide in the presence of a base such as potassium carbonate. Further modification of XXIX to XXX is carried out according to the general procedures described for the preparation of X from IX (Scheme I). 
Scheme 8 describes the preparation of intermediates represented by the formulae XXXIII and IV. The starting materials (amino phenols and alkyl derivatives represented by the formula VIb) are prepared according to the procedure as described in literature such as U.S. Pat. No. 4,670,046 (1987) which upon treatment with phthalic anhydride in acetic acid can afford phthalimide derivative (XXXI). Nitration of XXXI can be carried out by its addition to a mixture of sulfuric acid and nitric acid (9:1) at xe2x88x9215 to xe2x88x9230xc2x0 C. followed by addition of water and extraction of the product (XXXII) in organic solvents such as ethyl acetate or ether. XXXII can be reduced to the corresponding amine (XXXIII) by conventional methods such as treatment with iron in acetic acid or ethanolic hydrochloric acid or by catalytic hydrogenation in the presence of palladium on carbon. Amino group of XXXIII can be derivatized as described before in Scheme 1 to furnish XXXIV which in turn can be deprotected to finish XXXV. Removal of the protecting phthalimido group can be accomplished by several methods such as treatment with hydrazine in a polar solvent such as dimethylsulfoxide or by treatment with on organic amine such as methyl amine in ethanol. XXV can then be derivatized to the desired compound (X) according to the known procedures as described before in Scheme 1. Alternatively, XXXII can first be subjected to deprotection to afford the amine IV which can be modified to introduce the heterocyclic ring such as the uracil ring (U in XXXVI) according to the known procedures. Nitro group in XXXVI can then be reduced to afford the amine which can then be derivatized as described previously to afford X. 
Scheme 9 delineates a process for the preparation of the intermediates represented by the formula V. Starting materials represented by the formula XXXIX are prepared by the nitration of XXXVII which gives XXXVIII which can be reduced to XXXIX according to the literature procedure of Japanese patent 01 186849 (1989). The amino group in XXXIX is protected by forming amide or carbamate XL and the latter is nitrated to give XLI. Deprotection of XLI leads to the ortho-nitro aniline V. V can be converted into the desired compounds represented by XLV according to the procedures as shown in the scheme. 
Scheme 10 describes the preparation of intermediate represented by the formulae XLVIII. The starting material (XLVI) can be prepared according to the method described in patents, such as U.S. Pat. No. 5,154,755 (1992). XLVI reacts with ethyl chloroformate at basic condition to give the carbamate XLVII. The latter is nitrated with a mixture of nitric acid and sulfuric acid to give the intermediate XLVIII which can be N-alkylated with an alkylhalide in the presence of base to furnish XLIX. 
Scheme 11 describes an alternative procedure for the preparation of compounds represented by the formula LVII with varying R groups. Reduction of L to LI is carried out using conventional procedures such as catalytic reduction or iron-acetic acid mixture. The aniline LI is reacted with phenyl chloroformate to afford a carbamate represented by the formula LII which is nitrated with an inorganic salt such as ammonium or potassium nitrate in an acid anhydride such as acetic anhydride according to published perocedure such as described in WO 97/42188. Resultant nitro derivative LIII is cyclized to furnish the uracil derivative LIV upon reaction with an appropriately substituted amino crotonate in the presence of an inorganic or organic base exemplified by 1,8-diazabicylo[5.4.0]undec-7-ene (DBU). LIV is N-derivatized to afford LV followed by reduction to aniline LVI according to conventional procedures as described before. LVII is then derivatized to afford the final compounds represented by the formula LVII according to the procedures as described before. 
Scheme 12 desribes a process for the preparation of compounds represented by the formula LXII which are trisubstituted phenyl derivatives. Ortho-nitroaniline derivatives represented by the formula LVIII are the starting materials which are converted to a ortho-nitro uracil derivatives (LX) according to previously described procedures, e.g. via the NH uracil derivative (LIX). Nitro groups is then converted to an amino group (LXI) via conventional reduction procedures such as cataytic or iron-acetic acid reduction followed by derivatization to furnish LXII. 
Scheme 13 describes a procedure for the preparation of trisubstituted phenyl derivatives represented by the formula LXVI. Direct nitration of LXIII, where X and Q (a heterocylce) are as previously defined, using nitration reagents such as nitric acid or a mixture of sulfuric acid-nitric acid leads to ortho-nitro compounds represented by the formula LXIV which are reduced to the corresponding aniline derivatives (LXV) by reduction procedures such as catatlytic reduction or iron-acetic acid. Aniline (LXV) is then derivatized to furnish LXVI. 
Scheme 14 delineates a procedure for the preparation of tetrasubstituted phenyl derivatives represented by the formula LXXIV. The process is akin to one described in scheme 11 for the prepration of pentasubstituted phenyl derivatives (LVII). The nitro intermediates (LXVII) are reduced to the anilines (LXVIII) via conventional procedures followed by derivatization to the phenyl carbamate (LXIX) by reaction with a phenylhaloformate. Nitration to LXX (inorganic nitrate-acid anhydirde) is followed by the uracil ring formation (appropriately substituted crotonate-DBU) (LXXI) and N-derivatization to furnish LXXII. Reduciton to the aniline (LXXIII) is carried out by procedures such as catalytic reduction or iron-acetic acid followed by derivatization to furnish LXXIV. 
Scheme 15 describes vaious procedures for the derivatization of the amino group in LXXV via diazonium salts represented by LXXVI. The diazonium salts are prepared by treatment of the aniline with an inorganic nitrite solution such as sodium or potassium nitrite in an acid such as sulfuric or hydrochloric acid or by treatment of the aniline with an organic nitrite such as t-butyl nitrite in an organic solvent such as acetonitrile. Reaction is carried out between 10-15xc2x0 C. which results in a stable solution of the diazonium salt which is reduced to the corresponding hydrazine derivative represented by the formula LXXVII by reducing agents exemplified by stannic chloride. Hydrazine derivatives are then derivatized to a variety of compounds represented by the formula (LXXXVI) via conventional reacions such as acylation, alkylation, Schiff base formation, etc. The diazonium group in LXXVI is replaced by a hydroxyl to furnish the corresponding phenol (LXXVIII) by its treatment with an aqueous solution of cuprous oxide in presence of cupric nitrate or cupric sulfate at ambient temperature. LXXVIII is then derivatized to furnish LXXXVI via conventional reactions such as acylation, alkylation, etc. Treatment to the diazonium salts (LXXVI) with disulfides (RSSR) leads to the formation of corresponding thioethers represented by the formula LXXIX which can be further modified according to conventional procedures leading to sulfur analogs represented by the formula LXXXVI. LXXVI can be treated with inorganic cyanides leading to the formation of cyano derivatives (LXXXI) which can be oxidized via conventional routes to furnish carboxylic acids (LXXXV) which can then be derivatized leading to LXXXVI. The diazonium group can also be replaced with an azido group furnishing LXXX. LXXVI can be treated with inorganic iodides to afford the iodo compounds (LXXXII) which can be converted to the corresponding aldehydes (LXXXIII) (which are also directly obtainable from LXXVI via conventional procedures). LXXXIII can be reduced to furnish corresponding benzyl alcohols (LXXXIV) which can be derivatized to LXXXVI. 
Scheme 16 describes an alternatived procedure for the formation of amides (XC). Reaction of the ortho-amino phenol LXXXVII with an aliphatic or aromatic acyl halide in an organic solvent such as 1,4-dioxane or tetrahydrofuran in the absence or presence of an inorganic or organic base such as potassium carbonate, sodium carbonate, or triethylamine, regioselectively leads to the formation of corresponding amide represented by the formula LXXXIX. LXXXIX can also be produced by the hydrolysis of a corresponding alkyl ether such as methyl ether (LXXXVIII) by treatment with strong Lewis acids such as boron tribromide or boron tribromide-dimethyl sulfide complex. Phenol group in LXXXIX is then derivatized by treatment with a halide in the presence of base such as sodium carbonate or potassium carbonate in an organic solvent such as as acetone, methyt-ethyl ketone, dimethylsulfoxide, or tetrahydrofuran at ambient to reflux temperatures. 
Scheme 17 describes a procedure for the preparation of pyridazinone derivatives represented by the formula XCVII and XCVIII. Desired starting pyridazinone derivatives represented by formula XCI and XCIV can be prepared according to the literature procedure of WO 97/07104. These compounds can be nitrated with nitric acid or a mixture of nitric acid and sulfuric acid at ambient temperature or at 0xc2x0 C. for 15xcx9c30 minutes. The products XCII and XCV are isolated by addition of ice followed by filtration. XCIII and XCVI can be prepared by the reduction with iron in acetic acid or in ethanolic hydrochloric acid. Methylation of XCIII can be carried out by reacting XCIII with methyl iodide in presence of a base at 50 to 120xc2x0 C. for 1xcx9c5 hours. Further modification of XCVI to XCVIII is carried out by treatment of the aniline with an organic nitrite (such as t-butyl nitrite) in an organic solvent (such as acetonitrile) and alkyl acrylate in the presence of copper(II) chloride. Modification of XCVI to XCVII is carried out by treatment of the aniline with an alkyl or aryl acid halide at 50 to 120xc2x0 C. for 1xcx9c5 hours. 
USPTO Backgrounds
USPTO Backgrounds