BACKGROUND OF THE INVENTION 6- (Perfluoroalkyl) uracil compounds which are useful as herbicidal agents and methods for their preparation are known in the art.

Although the methods described in the art are useful for the preparation of those compounds, there is ongoing research to discover new and improved methods for the preparation of 6- (perfluoroalkyl) uracil compounds.

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

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

SUMMARY OF THE INVENTION The present invention provides a new process for the preparation of 6- (perfluoroalkyl) uracil compounds having the structural formula I

wherein n is an integer of 1,2,3,4,5 or 6; Z is hydrogen or Cl-C6alkyl; and Q is a C1-C6alkyl group or an optionally substituted phenyl, benzyl, heteroaryl or methyleneheteroaryl group, which process comprises: (a) reacting a 2- (N, N-disubstituted) amino-4- (perfluoroalkyl)-1,3-oxazin-6-one compound having the structural formula II wherein <BR> <BR> zi and Z2 are each independently Cl-C8alkyl or Z1 and Z2 may be taken together with the atom to which they are <BR> <BR> attached to form a 4-to 7-membered ring wherein Zlz2<BR> <BR> is represented by- (CH2) 20 (CH2) 2-or- (CH2) m-where m is an integer of 3,4,5 or 6; and n is as described above, with an amine compound having the structural formula III

QNH, (III) wherein Q is as described above in the presence of an acid or base to form the 6- (perfluoroalkyl) uracil compound of formula I wherein Z is hydrogen; and (b) optionally alkylating the formula I compound wherein Z is hydrogen to form a formula I compound wherein Z is Cl-C6 alkyl.

DETAILED DESCRIPTION OF THE INVENTION In a preferred embodiment of the present invention, the 2- (N, N-disubstituted) amino-4- (perfluoroalkyl)-1,3- oxazin-6-one compound of formula II is reacted with the amine compound of formula III and the acid or base, preferably at a temperature ranging from about 20°C to 150°C, in the presence of a solvent.

In a more preferred embodiment of this invention, the 2- (N, N-disubstituted) amino-4- (perfluoroalkyl)-1,3- oxazin-6-one compound is reacted with the amine compound and the acid, preferably at a temperature ranging from about 20°C to 150°C, in the presence of a solvent.

Acids suitable for use in this invention include organic acids including, but not limited to, Ci-Cgalkanoic acids such as formic acid, acetic acid, propionic acid and the like; and mineral acids including, but not limited to, hydrochloric acid, sulfuric acid, phosphoric acid and the like. Preferred acids include acetic acid and propionic acid.

Bases suitable for use in the preparation of the formula I compounds include, but are not limited to, tri (Cl-C6alkyl) amines such as trimethylamine, triethylamine, tripropylamine, tributylamine,

diisopropylethylamine and the like; heterocyclic tertiary amines such as 1,8-diazazbicyclo [5.4.0] undec-7-ene (DBU), 1/5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4- diazabicyclo [2.2.2] octane, pyridine, substituted pyridines, quinoline, substituted quinolines and the like; and alkali metal C1-C6alkoxides such as potassium tert-butoxide, sodium tert-butoxide and the like.

Preferred second 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 the present invention include, but are not limited to, carboxylic acid amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; dialkyl sulfoxides such as dimethyl sulfoxide and the like; aromatic hydrocarbons such as toluene, benzene, xylenes, mesitylene and the like; halogenated aromatic hydrocarbons such as chlorobenzene, fluorobenzene and the like; aliphatic hydrocarbons such as pentane, hexane, heptane and the like; halogenated aliphatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; alkanoic acids such as formic acid, acetic acid, propionic acid and the like; ketones such as acetone, methyl ethyl ketone and the like; ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxy- ethane and the like; nitriles such as acetonitrile, propionitrile and the like; and water; and mixtures thereof. It should be understood that a solvent should be chosen which does not adversely react with the particular acid or base being used. For example, an alkanoic acid would generally not be chosen as the solvent when the base is present. It should also be understood that when an acid is present, the acid may also serve as the solvent. For example, an alkanoic acid such as acetic acid, propionic acid and the like may

serve as both the acid and the solvent in step (a) of the process of the present invention.

Alkylation procedures suitable for use in this invention include conventional procedures known in the art. In a preferred embodiment of this invention, the alkylation procedure comprises reacting the formula I compound wherein Z is hydrogen with an alkyl halide having the structural formula IV or a dialkylsulfate ester having the structural formula V in the presence of a base XZ or (IV) wherein X is chlorine, bromine or iodine, and Z is Ci-Csalkyl.

Bases suitable for use in the alkylation procedures of this invention include conventional bases known in the art including, but not limited to, alkali metal hydrides such as sodium hydride and the like; alkali metal C1-C6alkoxides such as potassium tert-butoxide, sodium tert-butoxide and the like; alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkaline earth metal hydroxides such as calcium hydroxide and the like; and alkaline earth metal carbonates such as calcium carbonate and the like.

Preferred formula II compounds for use in the process of this invention are those wherein n is 1; and Z, and Z2 are each independently Cl-C6alkyl.

More preferred formula II compounds for use in the preparation of 6- (trifluoromethyl) uracil compounds are those wherein n is 1; and Z1 and Z2 are the same and represent methyl or ethyl.

Preferred formula I compounds which may be prepared by the process of the present invention are those wherein n is 1; Z is hydrogen or C1-C4alkyl; Q is G is CH2 or a bond; Gi is cx, or N; G2 is CX4 or N; X1 is hydrogen, halogen or a C1-C6alkyl group optionally substituted with one epoxy group, X2 is hydrogen, halogen NRRl, C02R2, C (O) R3, OR4, SO2RS, SO2NR6R. C (RB) (OR9) 2, C (Rlo)=NOR11, C (R12) =C(R13)- C (OR14)=NOR15, CH20-NCO2Rls, 1,3-dioxolane optionally substituted with one Cl-C6alkoxy group or one or two Cl-C4alkyl groups, 1,3-dioxolinone optionally substituted with one Ci-C6alkoxy group or one or two Cl-C4alkyl groups, or Cl-C4alkyl optionally substituted with one Co, R2 group and one halogen atom, and X3 is hydrogen, halogen, Cl-C4haloalkyl, CO2R17. cyano, Cl-C4haloalkoxy, OR,,, or Cl-C4alkyl, or when X1 and X2 are taken together with the atoms to which

they are attached, they may form a five-or six- membered ring wherein XX or X2X1 is represented by: -OC (R20) (R21) 0-,-CH2S (O) pN (R22)-,-SC (R23) =N-,-CH=CH- CH (Rll) O-,-OC (O) N-,-SC(R24)=N-,-ON (R25) C(O)-, -OC (CO2R26) =C (R,,)-,-NC(R,g)-C(SR)-,-CH=C(CO,R,.)0-, -CH2CH(R31) O-or-OC (R32) (R33) C (O)-, or <BR> <BR> when X2 and X3 are taken together with the atoms to which they are attached, they may form a five-or six- membered ring wherein X2X3 or X3X2 is represented by: -NC(R34)=NC (S)-,-N(R35)N=C (R36)-,-N (R37) C (R38) =N-, -N (R38) C (O) CH20-,-N (R39) C (O) CH=CH-,-S-N=C (R40)-, -0-N=C (R41)-,-N=N-N (R42)-,-C (R43) (R44) C(O)N(R45)- or -N(R46)C(O)C (R47)(R48)-; <BR> <BR> X4 is hydrogen, halogen or OR19;<BR> <BR> <BR> X. is hydrogen or halogen; R, R56, R64, R69, R70, R77 and R91 are each independently hydrogen, SO2R49, Cl-C4alkyl, C3-C., cycloalkyl, C3-C6alkenyl, C3-C6alkynyl, phenyl or benzyl; R1 is hydrogen, SO2Rso, C(O)Rugi, amino or C1-C4alkyl optionally substituted with CO2R52 or C (O)R53; R2, R16, R17, R26, R30, R68, R75, R76, R82 and R88 are each <BR> <BR> independently hydrogen, C1-C8haloalkyl, C3-C8alkenyl,<BR> <BR> <BR> C3-C6alkynyl, phenyl, benzyl, furfuryl, pyridyl, thienyl, C1-C8alkyl optionally substituted with CO2R54, morpholine or C (O) Rss, or an alkali metal, an alkaline earth metal, ammonium or organic ammonium cation; R3'R66, R67, R81, R8s and R89 are each independently hydrogen, C1-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, NR56R57, phenyl or benzyl; <BR> <BR> <BR> R4, R18, R19 and R65 are each independently hydrogen,<BR> <BR> <BR> Cl-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, Cl-C4haloalkyl, C(O)R58, C (S) R,, or benzyl;

RS and R72 are each independently C1-C6alkyl, C1-<BR> <BR> <BR> C6haloalkyl,<BR> <BR> <BR> NR60R61, imidazole or indazole;<BR> <BR> R6, R11, R12, R14, R15, R20, R21, R22, R25, R28, R29, R31, R32, R33, R35, R45, R46, R63 and R80 are each independently hydrogen or C1-C4alkyl; R7 is hydrogen, C3-C6alkenyl, C3-C6alkynyl, benzyl, or Cl-C4alkyl optionally substituted with cyano or C (0) R62; R8 and R2. are each independently hydrogen, C1-C4alkyl or <BR> <BR> Cl-C4alkoxy;<BR> <BR> <BR> R9 and Rgo are each independently C1-C6alkyl; Rio is hydrogen, Cl-C6alkyl, phenyl or benzyl; R13, R24 and R36 are each independently hydrogen, C1-C6alkyl or halogen; R23 is hydrogen or NR63R64; R34 is hydrogen, C1-C4alkyl or Cl-C4haloalkyl; R37 is hydrogen, Cl-alkyl or C2-C8alkoxyalkyl; R38 and R39 are each independently hydrogen, C1-C4alkyl, C1-C4haloalkyl, C3-C6alkenyl or C3-C6alkynyl; R40, R41 and R42 are each independently hydrogen, halogen, cyano, OR65, C (O) R66, C (S) R6,, CO2R68, C (=NOR69), a C1-C8alkyl, C3-C7cycloalkyl, C2-C8alkenyl or C2-Cealkynyl group, wherein each group is optionally substituted with any combination of one to six halogen atoms, one to three Cl-Clo- alkoxy groups, one or two Cl-C6haloalkoxy groups, one or two NR70R7l groups, one or two S (O) qR72 groups, one or two cyano groups, one or two C3-C, cycloalkyl groups, one OSO2R73 group, one or two C (O) R74 groups, one or two CO2R75 groups, one or two C (O) SR. groups, one or two <BR> <BR> C (O) NR77R78 groups, one to three OR7. groups, one<BR> <BR> <BR> or two P (O) (OR80) 2 groups, one 1,3-dioxolane optionally substituted with one to three

C1-C4alkyl groups, or one 1,3-dioxane optionally substituted with one to three C,-c4alkyl groups, or phenyl or benzyl optionally substituted with any combination of one to three halogen atoms, one to three C1-C6alkyl groups, one to three Cl- C6alkoxy groups, one C3-C, cycloalkyl group, one Cl-C4haloalkyl group, one Cl-C4alkylthio group, one cyano group, one nitro group, one C(O)R81 group, one CO2R82 group, one OR83 group, one SR84 group, one C1-C6alkoxymethyl group, one hydroxymethyl group, one C3-C8alkenyloxymethyl group, or one Ci-Cghaloalkoxymethyl group; R431 and R48 are each independently hydrogen, C1-C4alkyl, C1-C4haloalkyl, C3-C6alkenyl, C3-C6alkynyl or C3-C, cycloalkyl, or R43 and R44 or R47 and R48 may be taken together with the atom to which they are attached to form a C3-C, cycloalkyl group; R49, R50 and R86 are each independently Cl-C6alkyl, NR93R94, Cl-C4haloakyl, C3-C6alkenyl, C3-C6alkynyl or benzyl; R51, R52, R53, r54, R55, R57, R58, R59, R60, R61, R62, R71, R73, R74, R78, R87 and R92 are each independently hydrogen, <BR> <BR> Cl-C6alkyl, C3-C7cycloalkyl, Cl-C6haloalkyl,<BR> <BR> <BR> C3-C6alkenyl, C3-C6alkynyl, phenyl or benzyl; R79, R83 and R84 are each independently hydrogen, C (O) R85, SO2R86, Cl-C6haloalkyl, C2-C6alkenyl, Cs-C8cycloalkenyl, C2-C6alkynyl, phenyl, benzyl, or C1-Cl0alkyl optionally substituted with one hydroxyl, benzyloxy, OC (O) R87, Cl-C6alkoxy, CO2R88, C(O)R89, C(OR90)2, C(O)NR91R92 or cyano group; <BR> <BR> R93 and Rg4 are each independently hydrogen, C1-C4haloalkyl, C2-C6alkenyl, C3-C8cycloalkyl, C1-C8alkyl optionally substituted with one or two Cl-C4alkoxy groups or one cyanoalkyl group, or benzyl or phenyl optionally substituted with any

combination of one to three halogen atoms, one to three C1-C4alkyl groups, one to three Cl-C4haloalkyl groups, one to three Cl-C4alkoxy groups, one to three C1-C4haloalkoxy groups, one cyano group or one nitro group, and when Rg3 and R94 are taken together with the atom to which they are attached, they form a 5-to 12- membered monocyclic or fused bicyclic, heterocyclic ring optionally substituted with one or more groups independently selected from halogen, cyano, nitro, amino, hydroxyl, Cl-C4alkyl, Cl-C4haloalkyl, Cl-C4alkoxy, Cl-C4haloalkoxy and Cl-C4haloalkylsulfonyl groups; and p and q are each independently 0,1 or 2; and the optical isomers, diastereomers and/or tautomers thereof.

Of these more preferred formula I compounds, the most preferred are those wherein Z is hydrogen or methyl; Xi is hydrogen, fluorine or C1-C3alkyl optionally substituted with one epoxy group; or, when Xi and X2 are taken together with the atoms to which they are attached, they may form a five-or six- membered ring wherein XX or X2Xlis represented by: -OC (R20) (R21) O-,-CH2S (O) pN (R22)-,-SC (R23) =N-, -CH=CH-CH (Rll) O-,-OC (O) N-,-SC (R24) =N-,-ON (R25) C (O)-, -OC (CO2R26) =CH-,-NC (R28) =C (SR29)-,-CH=C (CO2R30) O-, -CH2CH(R3l) O-or-OC (R32) (R33) C (0)- ; R, R64, R69 and R,, are each independently hydrogen, SO2R49 or Cl-C4alkyl; R2, R16, R17, R26, R30, R68, R75 R76, R82 and R88 are each independently hydrogen, C3-C6alkenyl or Cl-alkyl optionally substituted with CO2Rs4, morpholine or C (O) Rss ; R3, R66, R67, Rgg and Rg are each independently hydrogen,

Cl-alkyl or NR56R57;<BR> <BR> <BR> R4, R18 and Rl9 are each independently hydrogen, Cl-C4alkyl, Cl-C4haloalkyl, C (O) Rs8, C3-C4alkenyl or C-Calkynyl; R56 is S°2R49; <BR> <BR> R. 7 is hydrogen or Cl-C4alkyl;<BR> <BR> <BR> R. and R72 are each independently NR6oR6l or indazole; R6, R11, R12, R14, R15, R20, R21, R22, R25, R28, R29, R31, R32, R33, <BR> <BR> R35, R45, R46 and R80 are each independently hydrogen or<BR> <BR> <BR> methyl;<BR> <BR> R7 is Cl-C4alkyl optionally substituted with cyano or C (O) R62 i <BR> <BR> R8 is hydrogen or Cl-C4alkoxy;<BR> <BR> <BR> Rg and Rgo are each independently C1-C4alkyl; Rlo is hydrogen or Cl-C3alkyl; R13, R24 and R36 are each independently hydrogen or chlorine; <BR> <BR> <BR> R23 is NR63R64;<BR> <BR> <BR> R34 is Cl-C3haloalkyl; R37 is C2-C4alkoxyalkyl; R38 and R39 are each independently Cl-C3haloalkyl, Cl-C3alkyl or propargyl; R40, R41 and R42 are each independently hydrogen, C (O) R66, C (S)R67, CO2R68, C(=NOR69), C1-C3alkyl optionally substituted with any combi- nation of one or two halogen atoms, one or two Cl-C3alkoxy groups, one or two Cl-C3haloalkoxy groups, one SO2R72 group, one or two cyano <BR> <BR> groups, one C3-C5cycloalkyl group, one OSO2R73<BR> <BR> <BR> group, one C (O) R, 4 group, one CO2R75 group, one C (O)SR76 group, one C (O) NR77R, 8 group, one to two OR, groups, one P (O) (OR80) 2 group, one 1,3- dioxolane group or one 1,3-dioxane group, or phenyl optionally substituted with any combination of one halogen atom, one or two methyl groups,

one methoxy group, one halomethyl group or one OR83 group; <BR> <BR> <BR> R43i R44. R4, and R48 are each independently hydrogen or<BR> <BR> <BR> methyl, or R43 and R44 or R4, and R48 may be taken together with the atom to which they are attached to form a cyclopropyl group; <BR> <BR> R49, R50 and R86 are each independently Cl-C4alkyl or NR93R94; R51,R52, R53, R54, R55, R58, R60, R61, R62, R73, R74, R78 and R87, are each independently hydrogen, Cl-alkyl or Cl-C4halo- alkyl; <BR> <BR> <BR> Rvg and R83 are each independently hydrogen, C (O) R85,<BR> <BR> <BR> SO2R86, Cl-C4haloalkyl, C3-C4alkenyl or Cl-alkyl substituted with one OC (O) R87, CO2R88, C (O) R89, C(OR90)2 or cyano group; R93 and R94 are each independently hydrogen or Cl-C8alkyl; and p is 0,1 or 2.

The process of the present invention is especially useful for the preparation of 6- (trifluoromethyl) uracil compounds having the structural formula VI wherein Z is hydrogen or methyl; X5 is hydrogen or halogen;

R40 is hydrogen, C (O) R66, C (S)R67, CO2R68, Cl-C3alkyl optionally substituted with any combination of one or two halogen atoms, one or two Cl-C3alkoxy groups, one or two Cl-C3haloalkoxy groups, one SO2R72 group, one or <BR> <BR> <BR> two cyano groups, one C3-Cscycloalkyl group, one<BR> <BR> <BR> OSO2R78 group, one or two OR79 groups, one P (O) (ORBO) z group, one 1,3-dioxolane group or one 1,3-dioxane group, or phenyl optionally substituted with any combination of one halogen atom, one or two methyl groups, one methoxy group, one halomethyl group or one OR83 group; R66, R67, R85 and R89 are each independently hydrogen, Cl-C4alkyl or NR56R57; R56 is SO2R49 ; <BR> <BR> RS7 is hydrogen or C1-C4alkyl;<BR> <BR> <BR> R49 and R86 are each independently Cl-C4alkyl or NR93R94;<BR> <BR> <BR> Rg3 and Rg4 are each independently hydrogen or Cl-alkyl; R68 and R88 are each independently hydrogen, C3-C6alkenyl or C1-C4alkyl optionally substituted with CO2Rs4, morpholine or C (O) Rss; R54, R55, R60, R61, R73 and R87 are each independently hydrogen, C1-C4alkyl or Cl-C4haloalkyl; R72 is NR60R61 or indazole; <BR> <BR> <BR> R79 and R83 are each independently hydrogen C (O) Reg, SO2R86,<BR> <BR> <BR> C1-C4haloalkyl, C3-C4alkenyl or Cl-C3alkyl substituted with one OC (O)R87, CO2R88, C (O) R89, C(OR90)2 or cyano group; R80 is hydrogen or methyl; and Rgo is Cl-C4alkyl.

Exemplary of halogen hereinabove are fluorine, chlorine, bromine and iodine. The terms # halomethyl# , <BR> <BR> # Cl-C4haloalkylu, # C1-C8haloalkyl# , # C1-C3haloalkoxy# ,

% Cl-C4haloalkoxyu and? Cl-C8haloalkoxymethylu are defined as a methyl, Cl-C4alkyl, Cl-C8alkyl, Cl-C3alkoxy, Cl-C4alkoxy or Cl-Cealkoxymethyl group substituted with one or more halogen atoms. In formula I above, alkali metals include sodium, potassium and lithium, and alkaline earth metals include calcium and magnesium. Organic ammonium cations suitable for use in the present invention include, but are not limited to, a group consisting of a positively charged nitrogen atom joined to from one to four aliphatic groups, each containing from one to sixteen carbon atoms.

In formula I above, 5-to 12-membered monocyclic or fused bicyclic, heterocyclic rings include, but are not limited to, benzimidazole, imidazole, imidazoline-2- thione, indole, isatoic anhydride, morpholine, piperazine, piperidine, purine, pyrazole, pyrrole, pyrrolidine and 1,2,4-triazole rings wherein each ring is optionally substituted with one or more groups independently selected from halogen, cyano, nitro, amino, hydroxyl, Cl-C4alkyl, Cl-C4haloalkyl, Cl-C4alkoxy, Cl-C4haloalkoxy, or Cl-C4haloalkylsulfonyl groups.

Starting formula II 2- (N, N-disubstituted) amino-4- (perfluoroalkyl)-1,3-oxazin-6-one compounds may be prepared, as shown in Flow Diagram I, by reacting a ß- amino--(perfluoroalkyl)(perfluoroalkyl) acrylate compound having the structural formula VII with a phosgeniminium chloride compound having the structural formula VIII (see, Bull.

Soc. Chem. Belg., 101 (4), pp. 313-321 (1992)).

FLOW DIAGRAM I

Amine compounds having the structural formula IIIa wherein Xl, Xg and R40 are as described hereinabove, may be prepared, as shown in Flow Diagram II, by cyclizing a ketone of formula IX with sulfur and ammonium hydroxide or ammonia to form a nitrobenzisothiazole of formula X, and reducing the formula X compound using conventional reducing agents such as iron in acetic acid.

FLOW DIAGRAM II

Starting amine compounds having the structural formula IIIb

wherein Xi, xi and R41 are as described hereinabove, may be prepared, as illustrated in Flow Diagram III, by reacting a ketone of formula XI with hydroxylamine hydrochloride optionally in the presence of sodium acetate to form an oxime of formula XII, cyclizing the formula XII compound with a base such as potassium hydroxide to form a nitrobenzisoxazole of formula XIII, and reducing the formula XIII compound using conventional reducing agents such as tin (II) chloride in acetic acid.

FLOW DIAGRAM III FLOW DIAGRAM III (cont.) X NOH 02N3XsR4 Os N I R41 (XII) Base X1 0 2N R41 X5 o-N XS O (XIII) [H] X1 H2N/R41 X5 o, N i i xo (IIIb)

Alternatively, formula XIII nitrobenzisoxazole compounds may be prepared, as shown in Flow Diagram IV, by reacting a ketone of formula XIV with hydroxylamine hydrochloride optionally in the presence of a base such as sodium acetate to form an oxime of formula XV, cyclizing the formula XV compound with 1,1'-carbonyl- diimidazole in the presence of a base such as tri- ethylamine to form a benzisoxazole of formula XVI, and nitrating the formula XVI compound using conventional methods such as a nitric acid/sulfuric acid mixture.

FLOW DIAGRAM IV X1 0 1 R 41 xi oh (XIV) NH20H-HC1 xi nos /w X""OH I oHR4l base x V OH (XV) 0 X R41 (XVI) (XVI)| HNO3/H2S04X R4 (XVI) xi 02N/R41 X5 o, N 1 1 (XIII)

Intermediate compounds of formulas X and XIII wherein R40 and R41 are OR., may be prepared, as shown in Flow Diagram V, by nitrating a benzisoxazol-3-ol or benzisothiazol-3-ol of formula XVII with a conventional nitrating agent such as a nitric acid/sulfuric acid mixture to form a 5-nitrobenzisoxazol-3-ol or 5- nitrobenzisothiazol-3-ol of formula XVIII, and reacting the formula XVIII compound with an electrophile of formula XIX in the presence of a base such as potassium carbonate.

FLOW DIAGRAM V FLOW DIAGRAM V (cont.) Base XR65 (XIX) (X = Cl, Br or I) xi X1 \ I IN Xg J

Formula X and XIII intermediate compounds wherein Ro and R41 are Cl or Br may be prepared, as shown in Flow Diagram VI, by reacting a 5-nitrobenzisoxazol-3-ol or 5- nitrobenzisothiazol-3-ol of formula XVIII with phosphorous oxychloride, phosphorous oxybromide or phosphorous pentabromide.

FLOW DIAGRAM VI

Other methods for the preparation of formula IIIa and IIIb amine compounds will become apparent from the examples set forth below. In addition, certain compounds of formulas IIIa, IIIb, X and XIII may be converted into other compounds of formulas IIIa, IIIb, X and XIII by using conventional procedures known to those skilled in the art.

Other formula III amine compounds are known in the art and may be prepared according to the procedures described in EP 561319-A; EP 540023-A; EP 545206-A; EP 542685-A; EP 473551-A; EP 476697-A; EP 489480-A; EP 496595-A; EP 420194-A; EP 648749-A; EP 705829-A; EP 714602-A; JP 9241245; JP 9301973; U. S. 5,169,430; U. S. 5,310,723; U. S. 5,324,854; U. S. 5,391,541; U. S. 5,399,543; U. S. 5,484,763; U. S. 5,523,278; U. S. 5,602,077; U. S. 5,661,108; WO 93/14073; WO 94/10155; WO 94/24128; WO 91/07393; WO 91/107392; WO 95/04461;

WO 95/05079; WO 95/05080; WO 95/17096; WO 95/25725; WO 95/29168; WO 95/32952; WO 95/33746; WO 96/02518; WO 96/08151; WO 96/14315; WO 96/28442; WO 96/34859; WO 96/35679; WO 97/01541; WO 97/01542; WO 97/05118; WO 97/07105; WO 97/08170; WO 97/08171; WO 97/08953; WO 97/12884; WO 97/12886; WO 97/29094; WO 97/29105; WO 97/34484; WO 97/35845; WO 97/42176; WO 97/42188; WO 97/45418; WO 97/47607; WO 98/02422; WO 98/06706; WO 98/08824; WO 98/27057; WO 98/27067; WO 98/27082; and WO 98/27088, among others.

In order to facilitate a further understanding of this invention, the following examples are presented primarily for the purpose of illustrating more specific details thereof. The scope of the invention should not be deemed limited by the examples but encompasses the entire subject matter defined in the claims.

EXAMPLE 1 Preparation of 3-Isopropvl-6- (trifluoromethvl)- 2,4 (1H, 3H)-pyrimidinedione

CF3 CH N'W O-I-H T3 tCH3IN\ H3C CH3 H H CF3 N\ 'O 1MDBU! ! --- N\/CH3 Xylene ! t ! O CH3 Isopropylamine (1.2 g, 20.3 mmol) and 1,8-diazabi- cyclo [5,4,0] undec-7-ene (DBU, 6 mL) are added to a solution of 2-dimethylamino-4-trifluoromethyl-6H-1,3- oxazin-6-one (4.0 g, 19.2 mmol) in xylene (34 mL). The resultant reaction mixture is held at 100°C for 3 hours, cooled, washed with 5 wt. o HC1 (40 mL), and extracted with ethyl acetate. The combined organic extracts are concentrated and triturated with heptane. The solids are filtered and dried to give the title product as a yellow powder (2.3g, 54% yield, mp 127°-129°C) which is identified by 1H NMR (DMSO-d6) 8 6.11 (1H, s), 4.96 (1H, sp), 1.35 (6H, d); and 19F NMR 8-68.9 (s).

Using essentially the same procedure, but using the appropriate amine, the following compounds are obtained: Q Acid/Base Solvent m °CYield (%) (S)-(+)-CH (CH3) C2Hs DBU Xylene 92-95 27 (R)- (-)-CH (CH3) C2H5 DBU Xylene 94-97 19 < CH3CO2H CH3CO2H white powder 47 CH3CO2H Toluene 169-172 74 CH3 CH3co2H Toluene 219-222 78 I 00OCH3 N 3 EXAMPLE 2 Preparation of 3- [3- (6-Methoxy-3, 4-xylyl)-1,2- benzisothiazol-5-vll-6- (trifluoromethyl)-2,4 (1H, 3H)- pyrimidinedione

A mixture of 5-amino-3- (6-methoxy-3, 4-xylyl)-1,2- benzisothiazole (8.53 g, 30.0 mmol), 2-dimethylamino-4- (trifluoromethyl)-6H-1,3-oxazin-6-one (6.87 g, 33.0 mmol) and acetic acid is refluxed for 2 hours, cooled, and poured into water. The resultant aqueous mixture is filtered to obtain a solid. A solution of the solid in methylene chloride is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an oil. Column chromatography of the oil using silica gel and a 5% diethyl ether in methylene chloride solution gives the title product as a yellow foam (8.37 g, 62.0%) which is identified by NMR spectral analyses.

Using essentially the same procedure, the following compounds are obtained: Xi Xs 40 mp °C H H CN 255-258 H H H >260 H H CH3 273-274 H H C2H5 CH 3 H H 230-231 OCH 3 c3 Cl 3 3 OCH3 OCH3 4 H H 1 125-130 OCH OCH3 H H >280 C Hs H H J 253-254 Xi Xs R o CH 3 H H ß 149-152 CH 3 OCH 3 H H OCH3 CH3 3 H3c CH 3 H H I OCH3OCH3 H H X OCH3 C H 2 5 H H ß OCH3 CH(CH3) 2 H H ß OCH 3 OCH H H < X, _5 40 mP °C H H I SCH OCH CL H H,, a H H) a OCH3 CH3 ci H H (wCl 208-210 OCH3 I H H OCH3 H H I/ OCH 3 X1 Xs 40 mP °C , (CH3) SOTCH3 H H Br F CH3 CH3 H F i/ OCH3 OCHg H F CH3 H H CH2CO2C2H5 H H Cl H H OCH2CN 254-258 H H OCH3 H H OCH (CH3) z 180-185 H H OCH2CH=CH2 210-212 H H OCH2CCH 212-215 H H OCH2CO2CH3 EXAMPLE 3 Preparation of 3- [3- (6-Methoxy-m-tolyl)-1,2- <BR> <BR> <BR> benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)- 2,4 (1H, 3H)-pyrimidinedione

A mixture of 3- [3- (6-methoxy-m-tolyl)-1,2-benziso- thiazol-5-yl]-6- (trifluoromethyl)-2,4 (lH, 3H)-pyrimidine- dione (160 g, 0.369 mol), potassium carbonate (76.6 g, 0.554 mol) and iodomethane (34.5 mL, 0.554 mol) in N, N- dimethylformamide is stirred at room temperature for 4 hours, and poured onto ice. The resultant aqueous mixture is extracted with methylene chloride. The organic extract is diluted with hexanes, washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title product as an orange foam (163 g, 98.8%) which is identified by NMR spectral analyses.

Using essentially the same procedure, the following compounds are obtained: Xi xs Z 4 mP °C H H CH3 H 223-225 H H CH3 CN 239-240 H H CH3 CH3 244-245 H H CH3 CH20CH2CO2CH3 143-144 H H CH3 C2Hs 171-172 CH H H CH3 198-200 OCH 3 I \ CaHs H H CH3 170.5-172 H H CH3 13 175.5-180 H H CH3 173-175 OCH3 Xi Xs Z R,, mp °C CH3 3 CH H H CH3 225-227 OCH I OCH3 ~ CH3 CH3 H H CH3 OCH 185-187 3 CH3 ? H H CH (CH3) 2 1- OCH CH3 CH 3 H H CH3 CH OCH3 CH3 CL CL x H3C CH3 H H CH3 H c CH 187-190 OCH 3 Xi X5 Z R o mp °C C2Hs I H H CH3 X 83-86 OCH 3 H H CH3 1 299 / N (CH3) SOzCFi3 I H H CH3 220-225 I H H CH3 fi ! 216-217 1 OCH3 CH(CH3) 2 1 I H H CH3 JX 103-105 OCH 3 X, X5 Z R,. mp °C CH3 3 H H CH2CH3; OCH oc3 CH3 3 H H C2Hs j41 105-107 OCH 3 OCH3 H H CH3) g H H CH3 I / SCH 3 H H CH3, J3\OCH3 147-149 3 OCH3 H H CH3 dq 170-172 I OCH3 Xi xs Z 40 mP °C CH 3 H H CH (CH3) z 151-154 OCH 3 Cl H H CH3 ? CH3 ci H H CH3 227-228 OCH3 H F CH3 CH3 CH3 H Cl CH3/ OCH3 Br F CH3 CH3 211-213 CH3 H F CH3 ¢) OCH3 H H CH3 CH2CO2c2Hs 150-152 H H CH3 Cl H H CH3 OCH2CN 265-266 H H CH3 OCH3 198-199 H H CH3 OCH (CH3) 2 125-127 H H CH3 OCH2CH=CH2 184-185 XiX, ZR,. mp °C<BR> <BR> <BR> <BR> H H CH3 OCH2C-CH 201-202. 5<BR> <BR> <BR> H H CH3 OCH2CO2CH3 181-183

EXAMPLE 4 Preparation of 3- [3- (6-Methoxy-m-tolyl)-1,2- benzisoxazol-5-vll-6- (trifluoromethyl)-2,4 (1H, 3H)- pyrimidinedione A mixture of 5-amino-3- (6-methoxy-m-tolyl)-1,2-benz- isoxazole (8.40 g, 0.033 mol), 2-dimethylamino-4- (tri- fluoromethyl)-6H-1,3-oxazin-6-one (7.60 g, 0.036 mol), and acetic acid is refluxed for three hours, cooled, poured onto ice, and diluted with water. The resultant aqueous mixture is filtered to obtain a solid. The solid is washed with water and dried to give the title product as a pink solid which is identified by NMR spectral analyses. Using essentially the same procedure, the following compounds are obtained: Xi Xs B41 mp °C H H 214-216 OCH3 H H ['J H H3 CH3 OCH Cl H OCH3 CH3 H F 4 H F I/ OCH3 H F CH3 235-237 H H CH3 283-285 H H Cl H H OCH2CO2CH3 180-182 H H OCH (CH3) 2 213-215 H H OCH3 230-235 Cl F CH3 125-130 EXAMPLE 5 Preparation of 3- [3- (6-Methoxy-m-tolyl)-1, 2- <BR> <BR> <BR> benzisoxazol-5-yl]-1-methyl-6-(trifluoromethyl)- 2,4 (lH, 3H)-pyrimidinedione

A mixture of 3- [3- (6-methoxy-m-tolyl)-1,2-benz- isoxazol-5-yl]-6- (trifluoromethyl)-2,4 (1H, 3H)-pyrimi- dinedione (10.5 g, 0.0255 mol) and potassium carbonate (7.04 g, 0.051 mol) in N, N-dimethylformamide is stirred for 15 minutes, treated with methyl iodide (7.24 g, 0.051 mol), stirred overnight, and poured onto ice. The resultant aqueous mixture is extracted with methylene chloride. The organic extracts are combined, washed with water, dried over anhydrous sodium sulfate, and concen- trated in vacuo to obtain a brown glass. Dry column chromatography of the glass using silica gel and a hexanes/ethyl acetate solution (3: 1) gives the title product as an off-white solid which is identified by NMR spectral analyses.

Using essentially the same procedure, the following compounds are obtained: Xi Xs R i mPC H H (; 1 H H OCH3 H H 225-226. 5 CH3 Cl Oh OCH3 CH3 H F H F I/, OCH3 H F H F OCH3 H F CH3 158-159 H H CH3 196-198 H H Cl 168.5-170 H H OCH2CO2CH3 156-157 H H OCH (CH3) 2 H H OCH3 160-161 Xi X, R,, mp °C Cl F CH3 154-155

EXAMPLE 6 Preparation of Ethyl 5-f3, 6-dihvdro-3-methvl-2,6- dioxo-4- (trifluoromethvl)-1 (2H)-pyrimidinyll-a, a- dimethvl-l, 2-benzisothiazole-3-acetate A mixture of ethyl 5-amino-a, a-dimethyl-1,2-benziso- thiazole-3-acetate (0.546 g, 2.06 mmol) and 2-dimethyl- amino-4- (trifluoromethyl)-6H-1,3-oxazin-6-one (0.430 g, 2.06 mmol) in acetic acid is refluxed for 4.5 hours,

concentrated in vacuo, and diluted with saturated sodium hydrogen carbonate solution. The resultant aqueous mixture is extracted with methylene chloride. The combined organic extracts are washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a brown foam. A solution of the foam in N, N- dimethylformamide is treated with potassium carbonate (0.312 g, 2.25 mmol), stirred for one hour, treated with iodomethane (0.420 mL, 6.70 mmol), stirred overnight at room temperature, and poured into an ice-water mixture containing 20 mL of concentrated hydrochloric acid. The resultant aqueous mixture is extracted with methylene chloride. The combined organic extracts are washed sequentially with 10% hydrochloric acid, water, saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a brown oil. Column chromatography of the oil using silica gel and a 33% ethyl acetate in methylene chloride solution affords a pink foam which is recrystal- lized from ethanol to give the title product as pink crystals, mp 164-167 °C.

EXAMPLE 7 Preparation of 2'-Chloro-2-methoxy-5-methvl-5'- nitrobenzcyphenone

A mixture of aluminum chloride (33.3 g, 25.0 mmol) in methylene chloride is cooled to about 5 °C, treated over one hour with p-methylanisole (31.6 g, 25.0 mmol) while maintaining the reaction mixture temperature below 10 °C, treated over 20 minutes with a solution of 2-chloro-5-nitrobenzoyl chloride (50.0 g, 22.7 mmol) in methylene chloride while maintaining the reaction mixture temperature below 10 °C, warmed to and stirred at room temperature for 60 minutes, and poured onto ice. The resultant aqueous mixture is treated with concentrated hydrochloric acid (50 mL) and extracted with methylene chloride. The organic extract is dried over anhydrous magnesium sulfate and concentrated in vacuo to give a yellow solid. After placing the solid in a Kugelrohr apparatus at 40 °C to remove residual p-methylanisole, the title product is obtained as a beige solid (68.8 g, 99.1W) which is identified by NMR spectral analyses. Using essentially the same procedure, the following compounds are obtained: X3 X5 W W1 W2 W3 W4 mp °C Cl H Cl H H I H H OCH3 115-116.5 Cl H H H CH3 H OCH3 Cl H H H C2H5 H H Cl H H CH3 CH3 H OCH3 Cl H H H OCH3 H H 108-112 Cl H H C2H5 H H OCH3 98-99.5 Cl H H H OCH3 H CH3 91-92 Cl H H H CH3 H H 95.5-96.5 Cl H H H SCH3 H H 127-128 Cl H H H CH3 H OCH3 91-92.5 Cl H H H C2H5 H H Cl H H H Cl H H 88.5-90.5 Cl H H H F H H 68-69.5 Cl H H Cl H H OCH3 124-126 Cl H H OCH3 H H OCH3 71-73 Cl H H H OCH3 H OCH3 98-100 Cl H H CH3 CH3 H OCH3 127-129 Cl H H H Cl H OCH3 96-99 <BR> <BR> <BR> Cl H CH3 H CH3 H OCH3 108.5-110 Cl H H H H CH3 OCH3 71-74 Cl H H H N (CH3) SOCH3 H H XsXgWWiWWWmp°C<BR> <BR> <BR> <BR> <BR> <BR> <BR> ClHHCHClHOCH 126-128 Cl H H CH3 H CH3 OCH3 110-112 Cl H CH3 CH3 CH3 H OCH3 104-106 <BR> <BR> Cl H H CH (CH3) 2 H H OCH3 69-71<BR> <BR> <BR> <BR> <BR> <BR> Cl H H CH3 H H H Cl H H H H H CN C1 H H H H H OCH3 Cl H H OCH3 H H H C1 H H F H H OCH3 Cl H H H F H OCH3 Cl H H H H H SCH3 Cl H H H H H CH3 Cl H H H H H F <BR> <BR> <BR> Cl H H SCH3 H H H<BR> <BR> <BR> <BR> <BR> <BR> Cl H H H OCH3 H H C1 H H -(CH2)3- H OCH3 Cl F H H H H H F F H CH3 H H OCH3

EXAMPLE 8 Preparation of 3- (6-Methoxy-m-tolvl)-5-nitro-l, 2- benzisothiazole Ammonium hydroxide (350 mL of a 30% solution, 270 mmol) is added to a mixture of 2'-chloro-2-methoxy-5- methyl-5'-nitrobenzophenone (68.7 g, 22.5 mmol) and sulfur (7.57 g, 23.6 mmol) in N, N-dimethylformamide. The resultant reaction mixture is 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 resultant aqueous mixture is filtered to obtain the title product as a yellow solid (63.5 g, 93.9%) which is identified by NMR spectral analyses.

Using essentially the same procedure, the following compounds are obtained: Wu, wi W2 mp C<BR> <BR> <BR> <BR> <BR> <BR> H H CH3 H OCH3 201-203<BR> <BR> <BR> <BR> <BR> H CH3 CH3 H OCH3 199-200 H CH3 H H H 116.5-117.5 <BR> <BR> <BR> H H Cl H OCH3 229-231<BR> <BR> <BR> <BR> <BR> H H H CH3 OCH3 134-136 H H H H CN 187.5-189 <BR> <BR> <BR> <BR> H H H H OCH3 193-198<BR> <BR> <BR> <BR> <BR> H H OCH3 H H 201-203<BR> <BR> <BR> <BR> <BR> H OCH3 H H H 174-175<BR> <BR> <BR> <BR> <BR> H F H H OCH3 224-226<BR> <BR> <BR> <BR> <BR> H C2H5 H H OCH3 153-154.5<BR> <BR> <BR> <BR> <BR> H H CH3 H H 188-189 H H N (CH3) SO2CH3 H H <BR> <BR> <BR> H CH3 C1 H OCH3 230-234 H I H H OCH3 H H SCH3 H H 177.5-178.5 <BR> <BR> <BR> H H OCH3 H CH3 131-135 H H F H H 226-228 <BR> <BR> <BR> <BR> H H Cl H H 217.5-219<BR> <BR> <BR> <BR> <BR> H H F H OCH3 224-225 H H H H SCH3 114.5-115.5 <BR> <BR> <BR> H H CH3 H OCH3 201-203<BR> <BR> <BR> <BR> <BR> H OCH3 H H OCH3 195-196 H H H H CH3 145-146 <BR> <BR> <BR> H H H H F 181-182 H H OCH3 H OCH3 171-172.5 H SCH3 H H H 139-140.5 W W1 W2 W3 W4 mp °C H CH3 H CH3 OCH3 CH3 CH3 CH3 H OCH3 <BR> <BR> <BR> H CH (CH3) 2 H H OCH3<BR> <BR> <BR> <BR> <BR> H H CH3 CH3 OCH3 H- (CH2) 3-H OCH3 and R40 mp°C H C (CH3)2CO2C2H5 75-77

EXAMPLE 9 Preparation of 3-Methyl-5-nitro-1,2-benzisothiazole

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

Using essentially the same procedure, the following compounds are obtained: H H C2H5 EXAMPLE 10 Preparation of 5-Amino-3- (6-methoxy-m-tolyl)-1,2- benzisothiazole

A mixture of 3-(6-methoxy-m-tolyl)-5-nitro-1,2- benzisothiazole (63.0 g, 0.210 mol), 5k acetic acid (1.52 L, 1.21 mol) and ethyl acetate (975 mL) is heated to 65 °C, treated portionwise with iron powder (58.6 g, 1.05 mol), stirred at 65 °C, and filtered through quartz filter paper. The filtrate phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phase and extracts are combined, washed

sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title product as an orange oil (55.7 g, 98.1%) which is identified by NMR spectral analyses.

Using essentially the same procedure, the following compounds are obtained: Xs R,. mp °C H H H CN 118.5-120 H CH3 112-113.5 H C2H5 CH 3 179-181 OCH 3 c2H5 H 90-91 H<C2H5 90-91CH3 F 4 OCH3 oc3 H", a 130-130. 5 R o CH3 3 g CH3 152-153 OCH 3 H 12 121. 5-123 SCH3 3 OCH3 3 H 108. 5-109.5 OCH3 H (¢J 158. 5-161 OCH 3 3 /101. 5-102.5 F H ¢9 104-105 CH3 3 OCH H 191-192. S OCH 3 SCH3 H A i Xs 40 mp °C OCH H t ; H H 128-129 H I OCH 3 I H 64 CH 3 SCH 3 H 108.5-109.5 ci H 133-134 F H 114.5-115 OCH H 1 152-153.5 CH3 cl F F H 4 146-147 OCH 3 Xs R40 M'P oc CH 3 3 H 60-65 OCH3 F H 143-145 OCH oc CH3 H t 100-101 H I / ci Cl 125-127 OCH3 cl H 1 172-174 OCH oc H 1 146-147 CN Xs 40 mP °C CH3 3 H 161-162 CH CH3 CH 3 H3 C CH H wW 173-175 OCH3 c2H5 H OCz3 CH(CH3) 2 H OCH 3 CH3 3 OCH3 NrN (CH3) S02CH3 H WJ F CH3 F < H C (CH3) 2CO2C2H5 5 40 mP °C H OCH2CN H OCH3 <BR> <BR> <BR> H OCH (CH3) 2<BR> <BR> <BR> <BR> <BR> H OCH2CH=CH2<BR> <BR> <BR> <BR> H OCH2C_CH<BR> <BR> <BR> <BR> <BR> H OCH2CO2CH3<BR> <BR> <BR> <BR> <BR> H CH2CO2C2H5

EXAMPLE 11 Preparation of 2-Chloro-2'-methoxv-5'-methvl-5- nitrobenzophenone, oxime A mixture of 2-chloro-2'-methoxy-5'-methyl-5-nitro- benzophenone (90.0 g, 0.294 mol) in ethanol is treated with a solution of hydroxylamine hydrochloride (102.3 g, 1.47 mol) in water, refluxed overnight, and poured onto ice. The resultant aqueous mixture is filtered to obtain a solid. The solid is washed with water and dried in a hot vacuum oven overnight to give the title product as a

white solid (84.2 g) which is identified by 1H NMR spectral analysis.

Using essentially the same procedure, the following compounds are obtained: X5 W W2 W, mp °C H OCH3 H H 173-178 H H H H 143-145 H H OCH3 H 191-192.5 H OCH3 H F H H OCH2CO2CH3 H 150-155 H OCH3 H CH3 185.5-186.5 F OCH3 H CH3 and mp 165-167°C EXAMPLE 12 Preparation of 3- (6-Methoxy-m-tolyl)-5-nitro-1, 2- benzisoxazole

A mixture of 2-chloro-2'-methoxy-5'-methyl-5-nitro- benzophenone, oxime (84.0 g, 0.262 mol) in ethanol is warmed to 65 °C, treated with 150 mL of 10% potassium hydroxide solution over 25 minutes, heated to 78 °C over one hour, cooled, and poured onto ice. The resultant aqueous mixture is filtered to obtain a solid. The solid is washed with water, dried, recrystallized from N, N- dimethylformamide, washed sequentially with N, N-dimethyl- formamide and ethanol, and dried in a vacuum oven at 80 °C to give the title product as a solid (mp 225-226 °C) which is identified by 1H NMR spectral analysis.

Using essentially the same procedure, the following compounds are obtained: Xs W W1 W2 me °C H OCH3 H H 170-171 H H H H 138-139 H H H OCH3 205-207 F OCH3 CH3 H and mp 84.5-86.5°C

EXAMPLE 13 Preparation of m-Fluorophenvl acetate

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

EXAMPLE 14 Preparation of 4'-Fluoro-2'-hydroxvacetophenone

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

EXAMPLE 15 Preparation of 4'-Fluoro-2'-hydroxvacetophenone, oxime

A mixture of 4'-fluoro-2'-hydroxyacetophenone (99.0 g, 0.640 mol), hydroxylamine hydrochloride (89.0 g, 1.28 mol), and sodium acetate (79.0 g, 0.960 mol) in methanol is refluxed for one hour and poured into an ice-water mixture. The resultant aqueous mixture is filtered to obtain a solid. The solid is dissolved in methylene chloride, and the resultant organic solution is dried over anhydrous magnesium sulfate, concentrated in vacuo, diluted with hexanes, and filtered to give the title product as a solid (55.0 g, mp 112-114 °C) which is identified by lH NMR spectral analysis.

EXAMPLE 16 Preparation of 6-Fluoro-3-methyl-1,2-benzisoxazole

A mixture of 4'-fluoro-2'-hydroxyacetophenone, oxime (47.0 g, 0.278 mol) in tetrahydrofuran is heated to just under reflux, treated with a solution of 1,1'-carbonyl- diimidazole (55.0 g, 0.340 mol) and triethylamine (39.0 g, 0.390 mol) in tetrahydrofuran, refluxed for one hour, cooled, concentrated in vacuo, and poured into an ice- water mixture. The resultant aqueous mixture is extracted with ether. The organic extracts are combined, washed sequentially with saturated ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an oil.

Column chromatography of the oil using silica gel and a methylene chloride/hexanes solution (1: 1) gives the title product as a yellow oil which is identified by 1H NMR spectral analysis.

EXAMPLE 17 Preparation of 5-Amino-6-fluoro-3-methyl-1,2-benz- isoxazole and 5-Amino-4-chloro-6-fluoro-3-methyl-1,2- benzisoxazole

A mixture of 6-fluoro-3-methyl-5-nitro-1,2-benz- isoxazole (3.00 g, 0.0153 mol) and acetic acid (85.0 mL) is heated to 40 °C, treated with a solution of tin (II) chloride dihydrate (9.70 g, 0.0430 mol) and concentrated hydrochloric acid (45.0 mL), refluxed for 90 minutes, concentrated in vacuo, neutralized with 2N sodium hydroxide solution and filtered to obtain a solid.

Column chromatography of the solid using silica gel and methylene chloride gives the title products as solids which are identified by NMR spectral analyses.

Using essentially the same procedure, the following compounds are obtained: X1 xs 41 H H CH3 H H Cl H H OCH2CO2CH3 H H OCH (CH3) 2 H H OCH (CH3) CO2CH3 H F OCH2CO2CH3 H H OCH3 CH3 H H I A OCH3 OCH3 cl3 Cl H OCH3 H Hua EXAMPLE 18 Preparation of 5-Nitro-1,2-benzisoxazol-3-ol

1,2-Benzisoxazol-3-ol (19.7 g, 0.146 mol) is added portionwise to concentrated sulfuric acid. The resultant

reaction mixture is treated dropwise with 70% nitric acid (11.3 mL), stirred for 90 minutes, and poured onto ice.

The resultant aqueous mixture is filtered to obtain a waxy paste. The paste is recrystallized from a methanol/water mixture to give the title product as a solid which is identified by 1H NMR spectral analysis.

Using essentially the same procedure, the following compounds are obtained: X5 4 Cl OH F OH F CH3 EXAMPLE 19 Preparation of Methyl [(5-nitro-1,2-benzisoxazol-3- yl) oxyl acetate

A mixture of 5-nitro-1,2-benzisoxazol-3-ol (3.90 g, 0.0220 mol) and potassium carbonate (4.17 g, 0.0300 mol) in N, N-dimethylformamide is stirred for 30 minutes, treated with methyl bromoacetate (3.96 g, 0.0260 mol), stirred overnight at room temperature, and poured into an acidic ice-water mixture. The resultant aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a yellow oil. Column chromatography of the oil using silica gel and a (1: 1) to (4: 1) methylene chloride/hexanes gradient gives the title product as a white solid (2.80 g, mp 72-73.5 °C) which is identified by NMR spectral analyses.

Using essentially the same procedure, the following compounds are obtained: XsR. imp °C<BR> <BR> H OCH (CH3) 2 81-83<BR> H OCH2CH=CH2 70-72<BR> H OCH3 101.5-103<BR> Cl OCH (CH3) CO2CH3 98-100<BR> F OCH2CO2CH3 104-106 EXAMPLE 20 Preparation of 3-Chloro-5-nitro-1,2-benzisoxazole

A mixture of 5-nitro-1,2-benzisoxazol-3-ol (4.00 g, 0.0220 mol) and phosphorus oxychloride (40.0 mL, 65.8 g, 0.429 mol) is placed in a glass bomb, heated at 150-155 °C for two hours, cooled overnight, concentrated in vacuo, diluted with methylene chloride, and brought to about pH 8 with sodium hydrogen carbonate solution. The phases are separated. The organic phase is washed sequentially 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 a methylene chloride/hexanes solution (1: 1) gives the title product as an amber oil which is identified by NMR spectral analysis.

EXAMPLE 21 Preparation of 2-Chloro-2'-methoxy-5-nitrobenzophen- one

A solution of 2-bromoanisole (27.9 g, 145 mmol) in diethyl ether is cooled to-70 °C, treated with butyllithium (64.0 mL, 160 mmol), stirred at-70 °C for one hour, treated with 0.5 M zinc chloride in tetrahydrofuran solution (320 mL, 160 mmol), stirred for one hour at-70 °C, warmed to about 0 °C, and concentrated in vacuo to obtain a yellow-green oil. A solution of the oil in tetrahydrofuran is treated sequentially with tetrakis (triphenylphosphine) palladium (0) (5.00 g, 4.35 mmol) and a solution of 2-chloro-5-nitrobenzoyl chloride (35.0 g, 159 mmol) in tetrahydrofuran, stirred for three days, and poured into 10-06 hydrochloric acid. The resultant aqueous mixture is extracted with methylene

chloride. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a semi-solid. The solid is triturated with diethyl ether to give the title product as a yellow solid which is identified by NMR spectral analyses.

Using essentially the same procedure, the following compounds are obtained: Wl W2 W3 W mp °C H Cl H OCH3 96-99 H H CH3 OCH3 71-74 F H H OCH3 Cl H H OCH3 124-126 OCH3 H H OCH3 71-73 H OCH3 H OCH3 98-100 H F H OCH3 H H CH3 H 65-66.5 H H SCH3 H 87-88 H H H F 118-120 H H H CH3 78-79.5 H H H SCH3 123-124.5 H F H H H H OCH3 H H H H OCH3 H CH3 CH3 OCH3 EXAMPLE 22 Preparation of 2-Chloro-2'-methoxy-5-nitrobenzhydrol

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

Using essentially the same procedure, the following compounds are obtained: w W3 4 OCH3 H OCH3 <BR> <BR> <BR> CH3 H OCH3<BR> F H OCH3 H OCH3 H EXAMPLE 23 Preparation of 2-Chloro-2'-methoxv-5-nitrobenzo- phenone

A solution of chromium (VI) oxide (91.0 g, 0.919 mol) in a water/acetic acid solution (1: 4) is added portionwise to 2-chloro-2'-methoxy-5-nitrobenzhydrol (64.2 g, 0.219 mol) while maintaining the reaction mixture temperature at 25 °C to 35 °C. The reaction mixture is then stirred at 25 °C to 35 °C for one hour, cooled, diluted with water, and concentrated in vacuo to obtain a residue. The residue is diluted with water, and

extracted with methylene chloride. The organic extracts are combined, dried over anhydrous sodium sulfate, mixed with silica gel (10 g), and filtered. The filtrate is concentrated in vacuo to obtain an oil. A solution of the oil in a methanol/water solution is decolorized with charcoal and concentrated in vacuo to yield a residue.

Column chromatography of the residue using silica gel and methylene chloride/hexanes solutions gives the title product as a white solid.

Using essentially the same procedure, the following compounds are obtained: W1 W3 4 mP °C OCH3 H OCH3 CH3 H OCH3 109-111 F H OCH3 94-95 H OCH3 H 79-81 EXAMPLE 24 Preparation of 2-Chloro-4-fluoro-5-nitrobenzovl chloride

A mixture of 2-chloro-4-fluoro-5-nitrobenzoic acid (50.0 g, 0.228 mol) and N, N-dimethylformamide (5 drops) in 1,2-dichloroethane is treated dropwise with oxalyl chloride (30.8 mL, 0.353 mol), refluxed for 3 hours, cooled, and concentrated in vacuo to obtain the title product as an orange solid which is identified by NMR spectral analyses.

EXAMPLE 25 Preparation of 2'-Chloro-4'-fluoro-5'-nitroaceto- phenone

A 2 M solution of methylzinc chloride in tetra- hydrofuran (5.00 mL, 10.1 mmol) is treated dropwise with a solution of 2-chloro-4-fluoro-5-nitrobenzoyl chloride (2.00 g, 8.40 mmol) in tetrahydrofuran, treated with tetrakis (triphenylphosphine) palladium (0) (0.400 g, 0.350 mmol), stirred at room temperature for one hour, and poured into 3 N hydrochloric acid. The resultant aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a dark liquid. Flash column chromatography of the liquid using silica gel and a methylene chloride in hexanes solution (6: 4) gives the title product as an off- white solid (mp 66-68 °C) which is identified by NMR spectral analyses.

EXAMPLE 26 Preparation of 6-Amino-3-methyl-5-nitro-1,2- benzisothiazole A mixture of 2'-chloro-4'-fluoro-58-nitroaceto- phenone (12.0 g, 0.0552 mol), sulfur (1.77 g, 0.0552 mol), 30% ammonium hydroxide solution (100 mL, 0.856

mol), and methanol is placed in a steel bomb, heated at 85 °C overnight, cooled, treated with additional sulfur (0.270 g) and 30% ammonium hydroxide solution (50 mL), heated at 85 °C overnight, cooled, filtered to remove solids, and extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Flash column chromatography of the solid using silica gel, and 0%, 1% and 2% diethyl ether in methylene chloride. solutions gives the title product as an orange solid (4.19 g, mp 189-191 °C) which is identified by NMR spectral analyses.

Using essentially the same procedure, the following compound is obtained: EXAMPLE 27 Preparation of 6-Chloro-3-methvl-5-nitro-1,2- benzisothiazole

A mixture of tert-butyl nitrite (3.30 mL, 0.0278 mol) and copper (II) chloride (2.98 g, 0.0222 mol) in acetonitrile is heated to 65 °C, treated portionwise with 6-amino-3-methyl-5-nitro-1,2-benzisothiazole (3.88 g, 0.0185 mol), stirred at 65 °C, cooled to room temperature, and poured into 20% hydrochloric acid. The resultant aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed with 20% hydro- chloric acid, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Flash column chromatography of the solid using silica gel and methylene chloride/hexanes solutions (1: 1 and 3: 1) gives the title product as a pale, yellow solid (2.54 g, mp 156-158 °C) which is identified by NMR spectral analyses.

Using essentially the same procedure, the following compound is obtained: EXAMPLE 28 Preparation of 6-Fluoro-3-methvl-5-nitro-1,2- benzisothiazole A mixture of 6-chloro-3-methyl-5-nitro-1,2- benzisothiazole (2.25 g, 9.80 mmol), potassium fluoride (2.85 g, 49.0 mmol), and 18-crown-6 (1.50 g, 5.70 mmol) in acetonitrile is heated in a sealed tube for 29 days,

filtered to remove solids, and partially concentrated in vacuo to obtain a liquid. The liquid is diluted with ethyl acetate, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a dark, brown solid. Flash column chromatography of the solid using silica gel and a 10% to 50% ethyl acetate in hexanes gradient gives a yellow solid containing two components. Flash column chromatography of the yellow solid using silica gel and a 50% to 70% methylene chloride in hexanes gradient gives the title product as a pale, yellow solid (0.870 g, mp 118-119 °C) which is identified by NMR spectral analyses.

Using essentially the same procedure, the following compound is obtained: EXAMPLE 29 Preparation of 2,2'-Dithiobis [5-nitrobenzoic acid]

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

EXAMPLE 30 Preparation of 5-Nitro-1,2-benzisothiazol-3 (2H)-one

A mixture of 2,2'-dithiobis [5-nitrobenzoic acid] (44.6 g, 0.113 mol) and thionyl chloride (49.0 mL, 0.670 mol) in methylene chloride is treated with N, N- dimethylformamide (0.800 mL), refluxed overnight, concentrated in vacuo, and diluted with 1,2- dichloroethane. The resultant organic solution is treated with bromine (22.5 mL, 0.436 mol), stirred at room temperature for 20 minutes, refluxed for 3.5 hours, and concentrated in vacuo to obtain a residue. A solution of the residue in 1,2-dichloroethane is cooled with an ice-water bath, treated with concentrated ammonia (112 mL) over 15 minutes, stirred at room temperature for 16 hours, cooled with an ice-water bath, and treated with concentrated hydrochloric acid. The resultant aqueous mixture is stirred at room temperature for one hour and filtered to obtain a solid. The solid is washed with

water and air-dried to give the title product as a yellow solid which is identified by NMR spectral analysis.

EXAMPLE 31 Preparation of 3-Chloro-5-nitro-1,2-benzisothiazole A mixture of 5-nitro-1,2-benzisothiazol-3 (2H)-one (10.0 g, 0.0510 mol), phosphorus oxychloride (40.0 mL, 0.429 mol) and tributylamine (12.0 mL, 0.050 mol) is heated at 103-115 °C for six hours, stirred at room temperature overnight, and poured into an ice-water mixture. The resultant aqueous mixture is extracted with methylene chloride. The combined organic extracts are washed sequentially with water and saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a gum.

Column chromatography of the gum using silica gel and methylene chloride gives the title product as an orange- yellow solid which is identified by NMR spectral analysis.

EXAMPLE 32 Preparation of Ethyl a-cvano-5-nitro-1,2-benziso- thiazole-3-acetate

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

EXAMPLE 33 Preparation of Ethyl 5-nitro-1,2-benzisothiazole-3- acetate

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

EXAMPLE 34 Preparation of 5-Nitro-1,2-benzisothiazole-3-aceto- nitrile

A mixture of ethyl 5-nitro-1, 2-benzisothiazole-3- acetate (5.00 g, 17.2 mmol), water (1.00 mL), and methyl sulfoxide (35.0 mL) is stirred at 107 °C for 24 hours, stirred at room temperature for two days, and poured into an ice-water mixture. The resultant aqueous mixture is stirred for two hours and filtered to obtain a solid.

The solid is washed with water and air-dried to give the title product as a tan solid.

EXAMPLE 35 Preparation of a, a-Dimethyl-5-nitro-1,2-benziso- thiazole-3-acetonitrile

A mixture of 5-nitro-1,2-benzisothiazole-3-aceto- nitrile (1.29 g, 5.89 mmol) in N, N-dimethylformamide is cooled to-9 °C, treated with sodium hydride (1.00 g of a 60% dispersion in oil), stirred at-3 °C for 20 minutes, treated with iodomethane (5.00 mL), stirred at room temperature for four hours, and poured onto ice. The resultant aqueous mixture is treated with 10% hydrochloric acid and extracted with methylene chloride.

The combined organic extracts are washed sequentially with water, saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a solid. column chromatography of the solid using silica gel and methylene chloride gives the title product as a yellow solid which is identified by NMR spectral analysis.

EXAMPLE 36 Preparation of Ethyl a, a-dimethyl-5-nitro-1,2-benz- isothiazole-3-acetate

A mixture of a, a-dimethyl-5-nitro-1,2-benzisothia- zole-3-acetonitrile (0.913 g, 3.69 mmol), water (0.450 mL), concentrated sulfuric acid (4.55 mL) and ethanol (9.10 mL) is refluxed for one hour, cooled, and poured onto ice. The resultant aqueous mixture is neutralized with saturated sodium bicarbonate solution and extracted with methylene chloride. The organic extract is washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a solid. Column chroma- tography of the solid using silica gel and methylene chloride gives the title product as pale yellow crystals.

EXAMPLE 37 Preparation of 5-Amino-3-chloro-1,2-benzisothiazole

A solution of 3-chloro-5-nitro-1,2-benzisothiazole (2.00 g) in toluene is treated with iron powder (8.40 g, 325 mesh) and concentrated hydrochloric acid (8 drops), heated to reflux, treated dropwise with water (8.00 mL), refluxed for 35 minutes, cooled to room temperature, and filtered through diatomaceous earth. The resultant filtrate is concentrated in vacuo to obtain a residue.

Flash column chromatography of the residue using silica gel and an ethyl acetate/hexanes solution (1: 1) gives the title product.

EXAMPLE38 Preparation of [ (5-Nitro-1, 2-benzisothiazol-3-vl)- oxylacetonitrile

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

Using essentially the same procedure, the following compounds are obtained: Ko mP °C OCH3 108-109 OCH(CH3) 2<BR> OCH2CH=CH2<BR> OCH2C=-CH 115-117<BR> OCH2CO2CH3

EXAMPLE 39 Preparation of 3-Chloro-5-nitro-1,2-benzisothiazole A suspension of 5-nitro-1,2-benzisothiazole (271 g, 1.50 mol) in acetic acid is heated to 80 °C to form a solution. The heating source is removed and chlorine gas is added continuously over six hours at 70-80 °C until saturation of the mixture occurs. The mixture is cooled to room temperature and stirred overnight. Filtration affords the title compound as a yellow crystalline solid (237 g, 73.6W) which is identified by NMR spectral analysis.

EXAMPLE 40 Preparation of 2'-Chloro-2-methyl-2-carboethox propiophenone

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

EXAMPLE 41 Preparation of 2'-Chloro-5'-nitro-2-methyl-2- carboethoxvpropiophenone To concentrated sulfuric acid (15.0 ml) at 5 °C is added 2'-chloro-2-methyl-2-carboethoxypropiophenone (4.00 g, 0.01570 mol) followed by dropwise addition of concentrated nitric acid (90%, 0.740 ml, 0.0204 mol).

After stirring 5 minutes, the mixture is poured onto ice and extracted with ethyl acetate. The organic layers are washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as a yellow oil (3.90 g, 83.0%) which is identified by NMR spectral analysis.

EXAMPLE 42 Preparation of 1-Benzothiophen-2,3-dione To a solution of thiophenol (100 g, 0.907 mol) in ether is added dropwise a solution of oxalyl chloride

(175 g, 1.38 mol) in ether. The mixture is stirred two hours at reflux and concentrated in vacuo. The residue is taken up in methylene chloride and cooled to 0 °C.

Aluminum chloride (145 g, 1.09 mol) is added in portions such that the temperature does not exceed 25 °C. The resultant mixture is stirred 30 minutes at reflux, cooled to room temperature and poured into ice water with stirring. The organic layer is washed with saturated sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to an orange solid which is recrystallized from methylene chloride: hexanes to afford the title compound (102 g, 69.0%) which is identified by NMR spectral analysis.

EXAMPLE 43 Preparation of 1,2-Benzisothiazole-3-carboxamide To ammonium hydroxide (1.78 1) is added 1- benzothiophen-2,3-dione (87.0 g, 0.530 mol) at 5-10 °C, followed by hydrogen peroxide (30% aqueous, 178 ml). The resultant mixture is filtered to obtain a yellow solid which is dried (77.0 g, 81.7%) and identified as the title compound by NMR and IR spectral analysis.

EXAMPLE 44 Preparation of 3-Cyano-5-nitro-1,2-benzisothiazole

A solution of 1,2-benzisothiazole-3-carboxamide (12.0 g, 0.0674 mol) in concentrated sulfuric acid at 0-5 °C is treated dropwise with nitric acid (90%, 4.12 ml) such that the temperature does not exceed 10 °C, stirred one hour at 5 °C, and poured into ice water with vigorous stirring. The resultant suspension is filtered to obtain a solid. The solid is dried and recrystallized from acetonitrile to afford a white solid (10.0 g) which is treated with phosphorus oxychloride (60.0 ml). The resultant mixture is 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.

Recrystallization of the solid from methylene chloride: hexanes gives the title compound as an orange solid (8.00 g, 87.9%, mp 168-170 °C) which is identified by NMR and IR spectral analyses.

EXAMPLE 45 Preparation of 2,4-Difluoro-5-nitrobenzoyl chloride

Oxalyl chloride (94.0 g, 0.739 mol) is added dropwise to a mixture of 2,4-difluoro-5-nitrobenzoic acid (100.0 g, 0.492 mol), methylene chloride and N, N- dimethylformamide (0.600 ml). The resultant mixture is stirred 3.25 hours at reflux, cooled to room temperature, and concentrated in vacuo to afford the title compound as a brown oil (111 g, 95.2%).

EXAMPLE 46 Preparation of 3- (6-Methoxv-m-tolvl)-6-amino-5- nitro-1,2-benzisothiazole

Ammonium hydroxide (330 ml) is added to a suspension of 2', 4'-difluoro-2-methoxy-5-methyl-5'-nitrobenzophenone (60.0 g, 0.186 mol), sulfur (6.25 g, 0.195 mol) and N, N- dimethylformamide on an ice bath. The resultant mixture is allowed to warm to 35 °C, heated gradually to 81 °C over a two hour period, cooled to room temperature, and poured into water. The resultant solid is taken up in ethyl acetate and N, N-dimethylformamide, and washed with water. The organic layer is concentrated in vacuo to afford the title compound which is identified by NMR spectral analysis.

EXAMPLE 47 Preparation of 3- (6-Methoxy-m-tolyl)-6-chloro-5- nitro-1,2-benzisothiazole CH3 on/ -I-tert-butyl nitrite + CuCl OCH3 H2N SoN OCH3 2 3 02N I I I OCH ci s, N 3 i

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

EXAMPLE 48 Preparation of 3- (6-Methoxv-m-tolvl)-6-fluoro-5- nitro-1,2-benzisothiazole CH3 pin/ KF + 18-crown-6 Cl S'N OCH3 Cl, i 3 02N/ CH3 Si

A mixture of 3- (6-methoxy-m-tolyl)-6-chloro-5-nitro- 1,2-benzisothiazole (7.30 g, 0.0218 mol), potassium fluoride (6.33 g, 0.109 mol) 18-crown-6 (2.31 g, 0.0872 mol) and sulfolane is stirred 19 hours at 154°C, cooled to room temperature, and poured into ice water. The resultant solid is filtered and chromatographed on silica gel with methylene chloride to afford a solid which is recrystallized from acetonitrile to afford a tan powder.

The powder is recrystallized from ethyl acetate to give the title compound as a tan solid (2.09 g, 29.9%) which is identified by NMR spectral analysis.

EXAMPLE 49 Preparation of 5-Amino-4-bromo-6-fluoro-3-methvl- 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 is added N-bromosuccinimide (0.586 g, 0.00329 mol) followed by 1,1'-azobis (cyclohexanecarbo- nitrile) (0.0200 g). The mixture is stirred two hours at 70 °C, additional N-bromosuccinimide (0.240 g, 0.00135 mol) is added, and the mixture is stirred 40 minutes at 70°C. The mixture is then cooled to room temperature, filtered and concentrated in vacuo to obtain a residue.

The residue is chromatographed on silica gel to give the title compound (0.870 g, 100*-.) which is identified by NMR spectral analysis.