 Process For The Preparation of 6-(Perfluoroalkyl)Uracil Compounds from Carbamate compounds
专利摘要:
An improved process is provided for preparing 6- (perfluoroalkyl) uracil compounds of formula (I) from carbamate compounds of formula (II). <Formula I> <Formula II> 公开号:KR20010114207A 申请号:KR1020017010394 申请日:2000-02-14 公开日:2001-12-31 发明作者:벤카타라만 카메스워랜 申请人:윌리암 에이취 캘넌, 에곤 이 버그；아메리칸사이아나미드컴파니； IPC主号:
专利说明:
Process for the preparation of 6- (perfluoroalkyl) Uracil Compounds from Carbamate compounds} [2] 6- (perfluoroalkyl) uracil compounds are useful as herbicides and methods for their preparation are known in the art. The 6- (perfluoroalkyl) uracil compound is prepared by reacting a 2- (N, N-disubstituted) amino-4- (perfluoroalkyl) -1,3-oxazin-6-one compound with an amine compound can do. [3] Bull. Soc. Chem. Belg., 101 (4), pages 313-321 (1992)] disclose 2- (N, N-di by reacting ethyl 3-amino-4,4,4-trifluorocrotonate with a phosgene iminium chloride compound. The preparation of alkyl) amino-4- (trifluoromethyl) -1,3-oxazin-6-one compounds is described. However, this method is not completely satisfactory because the required phosgene iminium chloride compound is difficult to handle and relatively expensive. Thus, preparation of 6- (perfluoroalkyl) uracil compounds avoiding the use of 2- (N, N-disubstituted) amino-4- (perfluoroalkyl) -1,3-oxazin-6-one compounds There is a need in the art for an improved method for. [1] An object of the present invention is 6- (perfluoroalkyl) which avoids the use of 2- (N, N-disubstituted) amino-4- (perfluoroalkyl) -1,3-oxazin-6-one compound. It is to provide an improved method for preparing uracil compounds. [4] Accordingly, it is an object of the present invention to avoid the use of 2- (N, N-disubstituted) amino-4- (perfluoroalkyl) -1,3-oxazin-6-one compounds for 6- (perfluoro To provide an improved process for the preparation of alkyl) uracil compounds. [5] Other objects and advantages of the invention will be apparent to those skilled in the art from the following description and claims. [6] Summary of the Invention [7] The present invention, [8] (a) reacting a carbamate compound of formula II with an amine compound of formula III in the presence of a base to yield 6- (perfluoroalkyl of formula I, wherein Y is hydrogen or C 1 -C 6 alkyl To produce uracil compounds, [9] (b) optionally alkylating a compound of formula I wherein Y is hydrogen to form a compound of formula I wherein Y is C 1 -C 6 alkyl [10] A novel process for the preparation of 6- (perfluoroalkyl) uracil compounds of formula (I) is provided. [11] [12] (Wherein [13] n is an integer of 1, 2, 3, 4, 5 or 6; [14] Y is hydrogen or C 1 -C 6 alkyl; [15] Q is a C 1 -C 6 alkyl group or an optionally substituted phenyl, benzyl, heteroaryl or methyleneheteroaryl group) [16] [17] Wherein Z and Z 1 are each independently C 1 -C 6 alkyl or a phenyl ring optionally substituted with any combination of 1 to 3 halogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl groups Benzyl, [18] n and Y are as mentioned above) [19] QNH 2 [20] (Wherein Q is as mentioned above) [21] In a preferred embodiment of the invention, the carbamate compound of formula II is reacted with an amine compound of formula III and a base, preferably in the presence of a solvent, at a temperature of about 20 ° C. to 150 ° C. [22] In another preferred embodiment of the invention, the double bond in the compound of formula (II) has a predominantly (Z) -configuration. [23] Advantageously, the present invention avoids the use of 2- (N, N-disubstituted) amino-4- (perfluoroalkyl) -1,3-oxazin-6-one compounds and 6- (perfluoroalkyl) Provided is an improved process for preparing uracil compounds. [24] The product, which is a compound of Formula I, can be isolated using conventional isolation methods such as diluting the reaction mixture with water and separating the product or extracting the product with a suitable extraction solvent. In the isolation method, conventional extraction solvents such as diethyl ether, ethyl acetate, toluene, methylene chloride and the like and mixtures thereof can be used. [25] Suitable bases for use in the process of the invention include tri (C 1 -C 6 alkyl) amines such as trimethylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, and the like; 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] heterocyclic tertiary amines such as octane, pyridine, substituted pyridine, quinoline, substituted quinoline and the like; And alkali metal C 1 -C 6 alkoxides such as potassium tert-butoxide, sodium tert-butoxide and the like. Preferred bases include 1,8-diazabicyclo [5.4.0] undec-7-ene and 1,5-diazabicyclo [4.3.0] non-5-ene. [26] Suitable solvents for use in step (a) of the process of the invention include carboxylic acid amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; Dialkyl sulfoxides such as dimethyl sulfoxide and the like; Aromatic hydrocarbons such as toluene, benzene, xylene, mesitylene and the like; Halogenated aromatic hydrocarbons such as chlorobenzene, fluorobenzene 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; Alcohols such as methanol, ethanol, n-propanol, sec-propanol and the like; Ketones such as acetone, methyl ethyl ketone and the like; Ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like; Nitriles such as acetonitrile, propionitrile and the like; And water; And mixtures thereof, but is not limited thereto. [27] Alkylation methods suitable for use in the present invention include conventional methods known in the art. In a preferred embodiment of the invention, the alkylation process of step (b) comprises reacting a compound of formula (I) wherein Y is hydrogen with an alkyl halide of formula (IV) or a dialkylsulfate ester of formula (V) in the presence of a base : [28] XY [29] [30] (Wherein [31] X is chlorine, bromine or iodine and Y is C 1 -C 6 alkyl) [32] Suitable bases for use in the alkylation process of the present invention include alkali metal hydrides such as sodium hydride and the like; Alkali metal C 1 -C 6 alkoxides 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; Common bases known in the art include, but are not limited to, alkaline earth metal hydroxides such as calcium hydroxide and the like. [33] Preferred compounds of formula II for use in the process of the invention [34] Y is hydrogen or C 1 -C 4 alkyl; [35] Z and Z 1 are each independently C 1 -C 4 alkyl; [36] n is 1; [37] More preferred carbamate compounds of formula (II) for use in the process of the invention, [38] n is 1; [39] Preferred compounds of formula (I) which may be prepared by the process of the invention, [40] n is 1; [41] Y is hydrogen or C 1 -C 4 alkyl; [42] Q is ego; [43] G is CH 2 or a bond; [44] G 1 is CX 5 or N; [45] G 2 is CX 4 or N; [46] X 1 is hydrogen, halogen or a C 1 -C 6 alkyl group optionally substituted with one epoxy group; [47] X 2 is hydrogen, halogen, NRR 1 , CO 2 R 2 , C (O) R 3 , OR 4 , SO 2 R 5 , SO 2 NR 6 R 7 , C (R 8 ) (OR 9 ) 2 , C ( R 10 ) = NOR 11 , C (R 12 ) = C (R 13 ) -C (OR 14 ) = NOR 15 , CH 2 O—NCO 2 R 16 , optionally one C 1 -C 6 alkoxy group or one or 1,3-dioxolane substituted with two C 1 -C 4 alkyl groups, 1,3-dioxolinone optionally substituted with one C 1 -C 6 alkoxy group or one or two C 1 -C 4 alkyl groups, Or C 1 -C 4 alkyl optionally substituted with one CO 2 R 2 group and one halogen atom, [48] X 3 is hydrogen, halogen, C 1 -C 4 haloalkyl, CO 2 R 17 , cyano, C 1 -C 4 haloalkoxy, OR 18 or C 1 -C 4 alkyl, or [49] X 1 and X 2 together with the atoms to which they are attached, X 1 X 2 or X 2 X 1 represents —OC (R 20 ) (R 21 ) O—, —CHS (O) p N (R 22 ) —, -SC (R 23 ) = N-, -CH = CH-CH (R 11 ) O-, -OC (O) N-, -SC (R 24 ) = N-, -ON (R 25 ) C (O )-, -OC (CO 2 R 26 ) = C (R 27 )-, -NC (R 28 ) = C (SR 29 )-, -CH = C (CO 2 R 30 ) O-, -CH 2 CH May form a 5- or 6-membered ring represented by (R 31 ) O- or -OC (R 32 ) (R 33 ) C (O)-, or [50] X 2 and X 3 together with the atoms to which they are attached, X 2 X 3 or X 3 X 2 is -NC (R 34 ) = NC (S)-, -N (R 35 ) N = C (R 36 ) -, -N (R 37 ) C (R 38 ) = N-, -N (R 38 ) C (O) CH 2 O-, -N (R 39 ) C (O) CH = CH-, -SN = C (R 40 )-, -ON = C (R 41 )-, -N = NN (R 42 )-, -C (R 43 ) (R 44 ) C (O) N (R 45 )-or -N May form a 5-6 membered ring represented by (R 46 ) C (O) C (R 47 ) (R 48 )-; [51] X 4 is hydrogen, halogen or OR 19 ; [52] X 5 is hydrogen or halogen; [53] R, R 56 , R 64 , R 69 , R 70 , R 77 and R 91 are each independently hydrogen, SO 2 R 49 , C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 6 Alkenyl, C 3 -C 6 alkynyl, phenyl or benzyl; [54] R 1 is hydrogen, SO 2 R 50 , C (O) R 51 , amino, or C 1 -C 4 alkyl optionally substituted with CO 2 R 52 or C (O) R 53 ; [55] R 2 , R 16 , R 17 , R 26 , R 30 , R 68 , R 75 , R 76 , R 82 and R 88 are each independently hydrogen, C 1 -C 8 haloalkyl, C 3 -C 8 alkenyl , C 3 -C 6 alkynyl, phenyl, benzyl, furfuryl, pyridyl, thienyl, C 1 -C 8 alkyl optionally substituted with CO 2 R 54 , morpholine or C (O) R 55 , or an alkali metal Alkaline earth metal, ammonium or organic ammonium cations; [56] R 3 , R 66 , R 67 , R 81 , R 85 and R 89 are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, NR 56 R 57 , Phenyl or benzyl; [57] R 4 , R 18 , R 19 and R 65 are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 1 -C 4 haloalkyl, C ( O) R 58 , C (S) R 59 or benzyl; [58] R 5 and R 72 are each independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, NR 60 R 61 , imidazole or indazole; [59] R 6 , R 11 , R 12 , R 14 , R 15 , R 20 , R 21 , R 22 , R 25 , R 28 , R 29 , R 31 , R 32 , R 33 , R 35 , R 45 , R 46 , R 63 and R 80 are each independently hydrogen or C 1 -C 4 alkyl; [60] R 7 is hydrogen, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, benzyl, or C 1 -C 4 alkyl optionally substituted with cyano or C (O) R 62 ; [61] R 8 and R 27 are each independently hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; [62] R 9 and R 90 are each independently C 1 -C 6 alkyl; [63] R 10 is hydrogen, C 1 -C 6 alkyl, phenyl or benzyl; [64] R 13 , R 24 and R 36 are each independently hydrogen, C 1 -C 6 alkyl or halogen; [65] R 23 is hydrogen or NR 63 R 64 ; [66] R 34 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; [67] R 37 is hydrogen, C 1 -C 4 alkyl or C 2 -C 8 alkoxyalkyl; [68] R 38 and R 39 are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 alkenyl or C 3 -C 6 alkynyl; [69] R 40 , R 41 and R 42 are each independently hydrogen, halogen, cyano, OR 65 , C (O) R 66 , C (S) R 67 , CO 2 R 68 , C (= NOR 69 ), C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl group, wherein C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl groups each have 1 to 6 halogen atoms, 1 to 3 C 1 -C 10 alkoxy groups, one or two C 1 -C 6 haloalkoxy groups, one or two NR 70 R 71 groups, one or two S (O) q R 72 groups, one or two cyano groups, one or two C 3 -C 7 cycloalkyl groups, one OSO 2 R 73 group, one or two C (O) R 74 groups, one or two CO 2 R 75 groups, one or two C (O) SR 76 groups, one or two C (O) NR 77 R 78 groups, one to three OR 79 groups , one or two P (O) (oR 80) 2 group, optionally one of the 1, 3-dioxolanyl optionally substituted with one to three C 1 -C 4 alkyl group solran, Righteousness being optionally substituted with one to three C 1 -C any combination of a single 1,3-dioxane substituted with 4 alkyl groups), or phenyl or benzyl (wherein the phenyl or benzyl are one to three halogen atoms, one To three C 1 -C 6 alkyl groups, one to three C 1 -C 6 alkoxy groups, one C 3 -C 7 cycloalkyl group, one C 1 -C 4 haloalkyl group, one C 1 -C 4 alkyl Thio group, one cyano group, one nitro group, one C (O) R 81 group, one CO 2 R 82 group, one OR 83 group, one SR 84 group, one C 1 -C 6 Optionally substituted with any combination of an alkoxymethyl group, one hydroxymethyl group, one C 3 -C 8 alkenyloxymethyl group, or one C 1 -C 8 haloalkoxymethyl group); [70] R 43 , R 44 , R 47 and R 48 are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl or C 3 -C 7 cycloalkyl, or R 43 and R 44 or R 47 and R 48 together with the atoms to which they are attached may form a C 3 -C 7 cycloalkyl group; [71] R 49 , R 50 and R 86 are each independently C 1 -C 6 alkyl, NR 93 R 94 , C 1 -C 4 haloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl or benzyl ; [72] R 51 , R 52 , R 53 , R 54 , R 55 , R 57 , R 58 , R 59 , R 60 , R 61 , R 62 , R 71 , R 73 , R 74 , R 78 , R 87 and R 92 Are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, phenyl or benzyl; [73] R 79 , R 83 and R 84 are each independently hydrogen, C (O) R 85 , SO 2 R 86 , C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 5 -C 8 cycloalkenyl , C 2 -C 6 alkynyl, phenyl, benzyl, or C 1 -C 10 alkyl (C 1 -C 10 alkyl is one hydroxyl, benzyloxy, OC (O) R 87 , C 1 -C 6 alkoxy, Optionally substituted with C0 2 R 88 , C (O) R 89 , C (OR 90 ) 2 , C (0) NR 91 R 92 or cyano group; [74] R 93 and R 94 are each independently hydrogen, C 1 -C 4 haloalkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkyl, wherein C 1 -C 8 alkyl Is optionally substituted with one or two C 1 -C 4 alkoxy groups or one cyanoalkyl group, or benzyl or phenyl, wherein benzyl or phenyl is one to three halogen atoms, one to three C 1 -C Of 4 alkyl groups, one to three C 1 -C 4 haloalkyl groups, one to three C 1 -C 4 alkoxy groups, one to three C 1 -C 4 haloalkoxy groups, one cyano group or one nitro group Optionally substituted in any combination) or R 93 and R 94 together with the atoms to which they are attached a 5-12 membered heterocyclic monocyclic or fused bicyclic heterocyclic ring (this heterocyclic ring); Rings are halogen, cyano, nitro, amino, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C Optionally substituted with one or more groups independently selected from 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy and C 1 -C 4 haloalkylsulfonyl groups; [75] p and q are each independently 0, 1 or 2, and their optical isomers, diastereomers and tautomers. [76] More preferred herbicides of formula (I) which may be prepared by the process of the invention [77] n is 1; [78] Y is hydrogen or methyl; [79] Q is ego; [80] G is CH 2 or a bond; [81] G 1 is CX 5 or N; [82] G 2 is CX 4 or N; [83] X 1 is hydrogen, fluorine or C 1 -C 3 alkyl (C 1 -C 3 alkyl is optionally substituted with one epoxy group), [84] X 2 is hydrogen, halogen, NRR 1 , CO 2 R 2 , C (O) R 3 , OR 4 , SO 2 R 5 , SO 2 NR 6 R 7 , C (R 8 ) (OR 9 ) 2 , C ( R 10 ) = NOR 11 , C (R 12 ) = C (R 13 ) -C (OR 14 ) = NOR 15 , CH 2 0-NCO 2 R 16 , 1,3-dioxolane (1,3-dioxolane Is optionally substituted with one C 1 -C 6 alkoxy group or one or two C 1 -C 4 alkyl groups), 1,3-dioxolinone (1,3-dioxolinone is one C 1 -C 6 Optionally substituted with an alkoxy group or one or two C 1 -C 4 alkyl groups), or C 1 -C 4 alkyl (C 1 -C 4 alkyl is optionally substituted with one CO 2 R 2 group and one halogen atom) ego, [85] X 3 is hydrogen, halogen, C 1 -C 4 haloalkyl, CO 2 R 17 , cyano, C 1 -C 4 haloalkoxy, OR 18 or C 1 -C 4 alkyl, or X 1 and X 2 are With the atoms to which they are attached, X 1 X 2 or X 2 X 1 is -OC (R 20 ) (R 21 ) O-, -CH 2 S (O) p N (R 22 )-, -SC (R 23 ) = N-, -CH = CH-CH (R 11 ) O-, -OC (O) N-, -SC (R 24 ) = N-, -ON (R 25 ) C (O)-, -OC (CO 2 R 26 ) = CH-, -NC (R 28 ) = C (SR 29 )-, -CH = C (CO 2 R 30 ) O-, -CH 2 CH (R 31 ) O- or -OC May form a five or six membered ring represented by (R 32 ) (R 33 ) C (O) —, or [86] X 2 and X 3 together with the atoms to which they are attached, X 2 X 3 or X 3 X 2 is -NC (R 34 ) = NC (S)-, -N (R 35 ) N = C (R 36 ) -, -N (R 37 ) C (R 38 ) = N-, -N (R 38 ) C (O) CH 2 0-, -N (R 39 ) C (O) CH = CH-, -SN = C (R 40 )-, -ON = C (R 41 )-, -N = NN (R 42 )-, -C (R 43 ) (R 44 ) C (O) N (R 45 )-or -N May form a 5- or 6-membered ring represented by (R 46 ) C (O) C (R 47 ) (R 48 )-; [87] X 4 is hydrogen, halogen or OR 19 ; [88] X 5 is hydrogen or halogen; [89] R, R 64 , R 69 and R 77 are each independently hydrogen, SO 2 R 49 or C 1 -C 4 alkyl; [90] R 1 is hydrogen, SO 2 R 50 , C (O) R 51 , amino or C 1 -C 4 alkyl (C 1 -C 4 alkyl is optionally substituted with CO 2 R 52 or C (O) R 53 ) ; [91] R 2 , R 16 , R 17 , R 26 , R 30 , R 68 , R 75 , R 76 , R 82 and R 88 are each independently hydrogen, C 3 -C 6 alkenyl or C 1 -C 4 alkyl ( C 1 -C 4 alkyl is optionally substituted with CO 2 R 54 , morpholine or C (O) R 55 ); [92] R 3 , R 66 , R 67 , R 85 and R 89 are each independently hydrogen, C 1 -C 4 alkyl, or NR 56 R 57 ; [93] R 4 , R 18 and R 19 are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C (O) R 58 , C 3 -C 4 alkenyl or C 3 -C 4 alkoxy Nil; [94] R 56 is SO 2 R 49 ; [95] R 57 is hydrogen or C 1 -C 4 alkyl; [96] R 5 and R 72 are each independently NR 60 R 61 or indazole; [97] R 6 , R 11 , R 12 , R 14 , R 15 , R 20 , R 21 , R 22 , R 25 , R 28 , R 29 , R 31 , R 32 , R 33 , R 35 , R 45 , R 46 And R 80 are each independently hydrogen or methyl; [98] R 7 is C 1 -C 4 alkyl, which is optionally substituted with cyano or C (O) R 62 ; [99] R 8 is hydrogen or C 1 -C 4 alkoxy; [100] R 9 and R 90 are each independently C 1 -C 4 alkyl; [101] R 10 is hydrogen or C 1 -C 3 alkyl; [102] R 13 , R 24 and R 36 are each independently hydrogen or chlorine; [103] R 23 is NR 63 R 64 ; [104] R 34 is C 1 -C 3 haloalkyl; [105] R 37 is C 2 -C 4 alkoxyalkyl; [106] R 38 and R 39 are each independently C 1 -C 3 haloalkyl, C 1 -C 3 alkyl or propargyl; [107] R 40 , R 41 and R 42 are each independently hydrogen, C (O) R 66 , C (S) R 67 , CO 2 R 68 , C (= NOR 69 ), C 1 -C 3 alkyl (C 1- C 3 alkyl is one or two halogen atoms, one or two C 1 -C 3 alkoxy groups, one or two C 1 -C 3 haloalkoxy groups, one SO 2 R 72 group, one or two cyano groups , One C 3 -C 5 cycloalkyl group, one OSO 2 R 73 group, one C (O) R 74 group, one CO 2 R 75 group, one C (O) SR 76 group, one C Of (0) NR 77 R 78 groups, one to two OR 79 groups, one P (O) (OR 80 ) 2 group, one 1,3-dioxolane group or one 1,3-dioxane group Optionally substituted with any combination), or phenyl (phenyl is optionally substituted with any combination of one halogen atom, one or two methyl groups, one methoxy group, one halomethyl group or one OR 83 group) ; [108] R 43 , R 44 , R 47 and R 48 are each independently hydrogen or methyl, or R 43 and R 44 or R 47 and R 48 together with the atoms to which they are attached may form a cyclopropyl group; [109] R 49 , R 50 and R 86 are each independently C 1 -C 4 alkyl or NR 93 R 94 ; [110] R 51 , R 52 , R 53 , R 54 , R 55 , R 58 , R 60 , R 61 , R 62 , R 73 , R 74 , R 78 and R 87 are each independently hydrogen, C 1 -C 4 alkyl Or C 1 -C 4 haloalkyl; [111] R 79 and R 83 are each independently hydrogen, C (O) R 85 , SO 2 R 86 , C 1 -C 4 haloalkyl, C 3 -C 4 alkenyl, or one OC (O) R 87 , CO 2 R 88 , C (O) R 89 , C (OR 90 ) 2 or C 1 -C 3 alkyl substituted with a cyano group); [112] R 93 and R 94 are each independently hydrogen or C 1 -C 8 alkyl; [113] p is a compound that is 0, 1 or 2. [114] The process of the invention is particularly useful for the preparation of 6- (trifluoromethyl) uracil compounds of formula VI: [115] [116] Where [117] Y is hydrogen or methyl; [118] X 5 is hydrogen or halogen; [119] R 40 is hydrogen, C (O) R 66 , C (S) R 67 , CO 2 R 68 , C 1 -C 3 alkyl (C 1 -C 3 alkyl is one or two halogen atoms, one or two C 1 -C 3 alkoxy group, one or two C 1 -C 3 haloalkoxy groups, one SO 2 R 72 group, one or two cyano groups, one C 3 -C 5 cycloalkyl group, one OSO 2 R Optionally substituted with any combination of 73 groups, one or two OR 79 groups, one P (O) (OR 80 ) 2 group, one 1,3-dioxolane group or one 1,3-dioxane group Or phenyl (phenyl is optionally substituted with any combination of one halogen atom, one or two methyl groups, one methoxy group, one halomethyl group or one OR 83 group); [120] R 66 , R 67 , R 85 and R 89 are each independently hydrogen, C 1 -C 4 alkyl or NR 56 R 57 ; [121] R 56 is SO 2 R 49 ; [122] R 57 is hydrogen or C 1 -C 4 alkyl; [123] R 49 and R 86 are each independently C 1 -C 4 alkyl or NR 93 R 94 ; [124] R 93 and R 94 are each independently hydrogen or C 1 -C 8 alkyl; [125] R 68 and R 88 are each independently hydrogen, C 3 -C 6 alkenyl or C 1 -C 4 alkyl (C 1 -C 4 alkyl optionally substituted with CO 2 R 54 , morpholine or C (O) R 55 ); [126] R 54 , R 55 , R 60 , R 61 , R 73 and R 87 are each independently hydrogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; [127] R 72 is NR 60 R 61 or indazole; [128] R 79 and R 83 are each independently hydrogen C (O) R 85 , SO 2 R 86 , C 1 -C 4 haloalkyl, C 3 -C 4 alkenyl, or one OC (O) R 87 , CO 2 R 88 , C (O) R 89 , C (OR 90 ) 2 or C 1 -C 3 alkyl substituted with a cyano group; [129] R 80 is hydrogen or methyl; [130] R 90 is C 1 -C 4 alkyl. [131] Examples of such halogens are fluorine, chlorine, bromine and iodine. The terms halomethyl, C 1 -C 4 haloalkyl, C 1 -C 8 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 4 haloalkoxy and C 1 -C 8 haloalkoxymethyl refer to one or more halogen atoms Substituted methyl, C 1 -C 4 alkyl, C 1 -C 8 alkyl, C 1 -C 3 alkoxy, C 1 -C 4 alkoxy or C 1 -C 8 alkoxymethyl groups. In the general formula (I), the alkali metal includes sodium, potassium, and lithium, and the alkaline earth metal includes calcium and magnesium. Organic ammonium cations suitable for use in the present invention include, but are not limited to, groups consisting of charged nitrogen atoms in amounts bonded to 1 to 4 aliphatic groups each containing 1 to 16 carbon atoms. [132] In Formula I, 5- to 12-membered monocyclic or fused bicyclic heterocyclic rings include benzimidazole, imidazole, imidazoline-2-thione, indole, isatoic anhydride, morpholine, pipepe Razine, piperidine, purine, pyrazole, pyrrole, pyrrolidine and 1,2,4-triazole rings are included, but are not limited to, each ring is halogen, cyano, nitro, amino, With one or more groups independently selected from hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, or C 1 -C 4 haloalkylsulfonyl groups Optionally substituted. [133] The carbamate compound of formula II, which is a starting material, can be prepared by reacting a β-amino-β- (perfluoroalkyl) acrylate compound of formula VII with a base and a chloroformate compound of formula VIII. [134] [135] (Where n, Y and Z 1 are as described above) [136] [137] Where Z is as defined above. [138] In addition, carbamate compounds of formula II are described in Tetrahedron Letters, No. 4, pages 243-246 (1976). [139] Β-amino-β- (perfluoroalkyl) acrylate compounds of formula (VII) are known in the art and described in U.S. Pat. 5,777,154; Journal of Heterocyclic Chemistry, 9, pages 513-522 (1972); And the English version of Institute of Chemistry, Urals Scientific Center, Academic of Sceinces of the USSR, Sverdlovsk, pages 1442-1447 (1987) -Zhurnal Organicheskoi Khimii, 22 (8), pages 1603-1609 (1986). Can be prepared accordingly. [140] Chloroformate compounds of formula (VIII) are known in the art and can be prepared by conventional methods. In addition, some chloroformate compounds of formula VIII are commercially available. [141] The amine compound of formula IIIa is cyclized to a ketone of formula IX with sulfur and ammonium hydroxide or ammonia to form nitrobenzisothiazole of formula X as shown in Scheme I, and a conventional reducing agent such as iron in acetic acid Can be prepared by reducing the compound of formula X. [142] [143] Wherein X 1 , X 5 and R 40 are as defined above. [144] [145] The starting amine compound of formula IIIb is reacted with a ketone of formula XI with hydroxylamine hydrochloride, optionally in the presence of sodium acetate, to form an oxime of formula XII, as shown in Scheme II, wherein the compound of formula XII is potassium hydroxide It may be prepared by cyclization with a base such as to form nitrobenzisoxazole of formula (XIII) and reducing the compound of formula (XIII) using a conventional reducing agent such as tin (II) chloride in acetic acid. [146] [147] Wherein X 1 , X 5 and R 41 are as defined above. [148] [149] [150] Alternatively, the nitrobenzisoxazole compound of formula (XIII) is reacted with 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) The compound of formula XV is cyclized to 1,1'-carbonyldiimidazole in the presence of a base such as triethylamine to form benzisoxazole of formula XVI, using conventional methods such as nitric acid / sulfuric acid mixtures. It can be prepared by nitrating the compound of formula XVI. [151] [152] Intermediate compounds of Formulas (X) and (XIII), wherein R 40 and R 41 are OR 65 , may form benzisoxazol-3-ol or benzisothiazol-3-ol of formula (XVII), such as a nitric acid / sulfuric acid mixture, Nitrification with a conventional nitrating agent to form 5-nitrobenzisoxazol-3-ol or 5-nitrobenzisothiazol-3-ol of formula (XVIII) and the compound of formula (XVIII) in the presence of a base such as potassium carbonate It can be prepared by reacting with an electrophile of Formula XIX. [153] [154] Intermediate compounds of formulas X and XIII wherein R 40 and R 41 are Cl or Br are 5-nitrobenzisoxazol-3-ol or 5-nitrobenzisothiazol-3-ol of formula XVIII as shown in Scheme V below. Can be prepared by reacting with phosphorus oxychloride, phosphorus oxybromide or phosphorus obromide. [155] [156] Other methods of preparing the amine compounds of formula IIIa and IIIb will be apparent from the examples below. In addition, some compounds of Formulas IIIa, IIIb, X, and XIII can be converted to other compounds of Formulas IIIa, IIIb, X, and XIII using conventional methods known to those skilled in the art. [157] Other amine compounds of formula III are known in the art, among others EP 561319-A; EP 540023-A; EP 545206-A; EP 542685-A; EP 473551-A; EP 476697-A; EP 489480-A; EP 496595-A; EP 420194-A; EP 648749-A; EP 705829-A; EP 714602-A; JP 9241245; JP 9301973; U.S. 5,169,430; U.S. 5,310,723; U.S. 5,324,854; U.S. 5,391,541; U.S. 5,399,543; U.S. 5,484,763; U.S. 5,523,278; U.S. 5,602,077; U.S. 5,661,108; WO 93/14073; WO 94/10155; WO 94/24128; WO 91/07393; WO 91/107392; WO 95/04461; WO 95/05079; WO 95/05080; WO 95/17096; WO 95/25725; WO 95/29168; WO 95/32952; WO 95/33746; WO 96/02518; WO 96/08151; WO 96/14315; WO 96/28442; WO 96/34859; WO 96/35679; WO 97/01541; WO 97/01542; WO 97/05118; WO 97/07105; WO 97/08170; WO 97/08171; WO 97/08953; WO 97/12884; WO 97/12886; WO 97/29094; WO 97/29105; WO 97/34484; WO 97/35845; WO 97/42176; WO 97/42188; WO 97/45418; WO 97/47607; WO 98/02422; WO 98/06706; WO 98/08824; WO 98/27057; WO 98/27067; WO 98/27082; And the methods described in WO 98/27088. [158] In order to facilitate a deeper understanding of the invention, the following examples are presented with the purpose of illustrating more specific details. The scope of the invention should not be construed as limited to the following examples but includes all subject matter as defined in the claims. [159] Example 1 [160] Preparation of ethyl 3-[(ethoxycarbonyl) amino] -4,4,4-trifluorocrotonate (Z)-(array) [161] [162] At 0 ° C. under nitrogen, a solution of 3-amino-4,4,4-trifluorocrotonate (18.3 g, 100 mmol) in N, N-dimethylformamide (30 ml) was added with N, N-dimethylformamide (20 ml Was added dropwise to a stirred mixture of sodium hydride (60% in mineral oil, 9.6 g, 240 mmol) in (). When stopping the release of hydrogen gas, an ethyl chloroformate (13.02 g, 120 mmol) in anhydrous ether (30 ml) was added. The solution was added at 0 ° C. over 30 minutes. The resulting reaction mixture was then stirred at rt for 1 h and quenched with water and ethyl acetate. The resulting mixture was extracted with ethyl acetate. The organic extract was washed with water and then with aqueous 2N hydrochloric acid, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield a residue. Fractional distillation of the residue under reduced pressure yielded the title compound as a liquid (bp 95-97 ° C. (4.5 mm) to 18 g (70.5% yield)) and confirmed by 1 H and 19 F NMR spectral analysis. [163] Example 2 [164] Preparation of ethyl 3-[(N-ethoxycarbonyl) -N-methylamino] -4,4,4-trifluorocrotonate (Z)-(array) [165] [166] At −10 ° C. under nitrogen, a solution of 3-methylamino-4,4,4-trifluorocrotonate (9.86 g, 50 mmol) in N, N-dimethylformamide (30 ml) was added to N, N-dimethylformamide. (30 ml) was added dropwise to a stirred mixture of sodium hydride (60% in mineral oil, 4.5 g, 112 mmol). The resulting mixture was stirred at 0 ° C. for 2 hours, treated with a solution of ethyl chloroformmate (8.14 g, 75 mmol) in anhydrous ether (40 ml) for 40 minutes at −10 ° C., stirred overnight at room temperature, water and ethyl acetate Quenched with The resulting mixture was extracted with ethyl acetate. The organic extract was washed with water and then with aqueous 2N hydrochloric acid, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield a residue. Fractional distillation of the residue under reduced pressure afforded the title compound as a liquid (bp 60-62 ° C. (0.2 mm) as 6.5 g (48.3%)) and confirmed by 1 H and 19 F NMR spectral analysis. [167] Example 3 [168] Preparation of 3-isopropyl-6- (trifluoromethyl) -2,4- (1H, 3H) -pyrimidinedione [169] [170] Ethyl 3-[(ethoxycarbonyl) amino] -4,4,4-trifluorocrotonate ((Z) -array) (2.04 g, 8 mmol) in xylene (15 ml), isopropylamine (0.567 g, 9.6 mmol) and a stirred mixture of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU, 1.46 g, 9.6 mmol) was heated at 100 ° C. for 3 hours, cooled, and ethyl acetate Diluted with. Water was added and the resulting aqueous mixture was extracted with ethyl acetate. The organic extracts were combined, washed with water and then with aqueous 2N hydrochloric acid, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a solid. The solid was crystallized from methanol / water to give the title compound as a solid (1.08 g (61% yield)) and confirmed by 1 H and 19 F NMR spectral analysis. [171] Example 4 [172] 3- [3- (6-methoxy-m-tolyl) -1,2-benzisothiazol-5-yl] -6- (trifluoromethyl) -2,4 (1H, 3H) -pyrimidine Preparation of Dion [173] [174] Ethyl 3-[(ethoxycarbonyl) amino] -4,4,4-trifluorocrotonate ((Z) -array) (2.04 g, 8 mmol) in xylene (15 ml), 5-amino-3- (6-methoxy-m-tolyl) -1,2-benzisothiazole (2.59 g, 9.6 mmol) and 1,8- (diazabicyclo [5.4.0] untech-7-ene (DBU, 1.46 g, 9.6 mmol) was heated for 6 h at 110 ° C., cooled, and quenched with ethyl acetate and water The resulting mixture was extracted with ethyl acetate The organic extracts were combined, washed with aqueous 2N hydrochloric acid, anhydrous sodium sulfate Dried over, filtered and concentrated in vacuo to give a foam Through flash chromatography of the foam with silica gel and ethyl acetate / hexane solution (3: 7) the title compound was solid (2.5 g (72% yield)). ) And confirmed by 1 H and 19 F NMR spectral analysis. [175] Example 5 [176] Preparation of 2'-chloro-2-methoxy-5-methyl-5'-nitrobenzophenone [177] [178] The mixture of aluminum chloride (33.3 g, 25.0 mmol) in methylene chloride is cooled to about 5 ° C. and treated with p-methylanisole (31.6 g, 25.0 mmol) over 1 hour while maintaining the reaction mixture at below 10 ° C. Treat the reaction mixture with a solution of 2-chloro-5-nitrobenzoyl chloride (50.0 g, 22.7 mmol) in methylene chloride over 20 minutes while maintaining the temperature below 10 ° C., warm to room temperature and stir at room temperature for 60 minutes. And poured on ice. The resulting aqueous mixture was treated with concentrated hydrochloric acid (50 ml) and extracted with methylene chloride. The organic extract was dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a yellow solid. This solid was placed in a Kugelrohr apparatus at 40 ° C. to remove residual p-methylanisole, and the title compound was obtained as a beige solid (68.8 g, 99.1%), which was confirmed by NMR spectral analysis. [179] Using the same method, the following compounds were obtained: [180] [181] [182] Example 6 [183] Preparation of 3- (6-methoxy-m-tolyl) -5-nitro-1,2-benzisothiazole [184] [185] 350 mL (270 mmol) of ammonium hydroxide (30% solution) was added to 2'-chloro-2-methoxy-5-methyl-5'-nitrobenzophenone (68.7 g, 22.5 mmol) in N, N-dimethylformamide and To a mixture of sulfur (7.57 g, 23.6 mmol) was added. The resulting reaction mixture was stirred at 80 ° C. for 19.5 hours, cooled to 40 ° C., treated with 50 mL of additional ammonium hydroxide (30% solution), stirred at 80 ° C. for 25 hours, cooled and poured onto ice It was. The resulting aqueous mixture was filtered to give the title compound as a yellow solid (63.5 g, 93.9%), which was confirmed by NMR spectral analysis. [186] Using the same method, the following compounds were obtained: [187] [188] [189] And [190] [191] Example 7 [192] Preparation of 3-methyl-5-nitro-1,2-benzisothiazole [193] [194] Ammonia (45 g, 2.642 mmol) was bubbled into methanol in a still bomb at −40 ° C. Then sulfur (30.5 g, 95.0 mmol) and 2'-chloro-5'-nitroacetophenone (19 g, 95.0 mmol) were added. The spring was sealed and heated at about 90 ° C. overnight. After cooling, the reaction mixture was removed from the spring and concentrated in vacuo to give a residue. This residue was diluted with methylene chloride, passed between silica gel plugs and concentrated in vacuo to afford the title compound as an orange solid (12.0 g), which was confirmed by NMR spectral analysis. [195] Using the same method, the following compounds were obtained: [196] [197] [198] Example 8 [199] Preparation of 5-amino-3- (6-methoxy-m-tolyl) -1,2-benzisothiazole [200] [201] 3- (6-methoxy-m-tolyl) -5-nitro-1,2-benzisothiazole (63.0 g, 0.210 mol), 5% acetic acid (1.52 L, 1.21 mol) and ethyl acetate (975 mL) The mixture of was heated to 65 ° C. and treated with iron powder (58.6 g, 1.05 mol) in portions, stirred at 65 ° C. and filtered through quartz filter paper. The filtrate phase was separated and the aqueous phase was extracted with ethyl acetate. The organic phases and extracts were combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound as an orange oil (55.7 g, 98.1%), which was confirmed by NMR spectral analysis. [202] Using the same method, the following compounds were obtained: [203] [204] [205] [206] [207] [208] [209] Example 9 [210] Preparation of 2-chloro-2'-methoxy-5'-methyl-5-nitrobenzophenone, oxime [211] [212] Mixture of 2-chloro-2'-methoxy-5'-methyl-5-nitro-benzophenone (90.0 g, 0.294 mol) in ethanol with a solution of hydroxylamine hydrochloride (102.3 g, 1.47 mol) in water Treated, refluxed overnight and poured on ice. The resulting aqueous mixture was filtered to give a solid. This solid was washed with water and dried overnight in a hot vacuum oven to afford the title compound as a white solid (84.2 g), which was confirmed by 1 H NMR spectral analysis. [213] Using the same method, the following compounds were obtained: [214] [215] And [216] [217] Example 10 [218] Preparation of 3- (6-methoxy-m-tolyl) -5-nitro-1,2-benzisoxazole [219] [220] A mixture of 2-chloro-2'-methoxy-5'-methyl-5-nitro-benzophenone, oxime (84.0 g, 0.262 mol) in ethanol is warmed to 65 ° C. and 10% potassium hydroxide solution over 25 minutes Treated with 150 mL, heated to 78 ° C. over 1 h, cooled and poured on ice. The resulting aqueous mixture was filtered to give a solid. The solid was washed with water, dried, recrystallized from N, N-dimethylformamide, washed sequentially with N, N-dimethylformamide and ethanol and dried in a vacuum oven at 80 ° C. to give the title compound as a solid ( mp 225-226 ° C.), which was confirmed by 1 H NMR spectral analysis. [221] Using the same method, the following compounds were obtained: [222] [223] And [224] [225] Example 11 [226] 5-amino-3- (6-methoxy-m-tolyl) -1,2-benzisoxazole and 5-amino-4-chloro-3- (6-methoxy-m-tolyl) -1,2- Preparation of Benzisoxazole [227] [228] 3- (6-methoxy-m-tolyl) -5-nitro-1,2-benzisoxazole in acetic acid (380 ml) [229] (20.0 g, 0.0703 mol) is warmed and treated with a warm solution of dihydrate (47.4 g, 0.210 mol) of tin chloride in concentrated hydrochloric acid (110 ml), refluxed for 1 hour, cooled to 10 ° C, Concentration in vacuo gave a gum. The gum was added to water under stirring to obtain a slurry. The slurry was treated with 80 g of 50% sodium hydroxide solution, stirred at 60 ° C. to 80 ° C. over 1 hour, cooled and decanted to give a residue. The mixture of residue in ethanol was treated with potassium hydroxide (10 g), heated overnight, cooled to room temperature, neutralized with hydrochloric acid and concentrated in vacuo to give a residue. The residue was diluted with ethyl acetate and filtered. The filtrate was concentrated in vacuo and chromatographed using 2% ethyl acetate solution in silica gel and methylene chloride to give the semisolid title compound, which was confirmed by elemental and mass spectral analysis. [230] Using the substantially same method, the following compounds were obtained. [231] [232] Example 12 [233] Preparation of m-fluorophenyl acetate [234] [235] The solution of 3-fluorophenol (100 g, 0.890 mol) in methylene chloride is cooled to 0-5 [deg.] C., treated with pyridine (75.0 mL, 0.930 mol), stirred for several minutes, and the reaction mixture is 17 [deg.] C. or lower. Acetyl chloride (66.0 mL, 0.930 mol) was added dropwise while maintaining at a temperature of 2, stirred at an ice bath temperature for 2 hours, warmed to room temperature and poured into an ice-water mixture. The organic phase was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound as a yellow oil, which was confirmed by 1 H NMR spectral analysis. [236] Example 13 [237] Preparation of 4'-fluoro-2'-hydroxyacetophenone [238] [239] m-fluorophenyl acetate (123 g, 0.798 mol) was cooled with an ice bath, treated with aluminum chloride (150 g, 1.12 mol) in portions, stirred at 190 ° C. for 1 hour, and cooled to give a solid. A mixture of ice, water and hydrochloric acid, and methylene chloride were added to the solid. The resulting mixture was stirred for a few minutes and the phases were separated. The organic phase was washed sequentially with water, saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound (99.0 g), which was confirmed by 1 H NMR spectral analysis. [240] Example 14 [241] Preparation of 4'-fluoro-2'-hydroxyacetophenone, oxime [242] [243] A mixture of 4'-fluoro-2'-hydroxyacetophenone (99.0 g, 0.640 mol), hydroxylamine hydrochloride (89.0 g, 1.28 mol), and sodium acetate (79.0 g, 0.960 mol) in methanol was added to 1 It was refluxed for hours and poured into an ice-water mixture. The resulting aqueous mixture was filtered to give a solid. This solid is dissolved in methylene chloride and the resulting organic solution is dried over anhydrous magnesium sulfate, concentrated in vacuo, diluted with hexanes and filtered to give the title compound as a solid (55.0 g, mp 112-114 ° C.), This was confirmed by 1 H NMR spectral analysis. [244] Example 15 [245] Preparation of 6-fluoro-3-methyl-1,2-benzisoxazole [246] [247] A mixture of 4'-fluoro-2'-hydroxyacetophenone, oxime (47.0 g, 0.278 mol) in tetrahydrofuran is heated to just before reflux and 1,1'-carbonyldiimidazole in tetrahydrofuran (55.0 g, 0.340 mol) and triethylamine (39.0 g, 0.390 mol) were treated, refluxed for 1 hour, cooled, concentrated in vacuo and poured into an ice-water mixture. The resulting aqueous mixture was extracted with ether. The organic extracts were combined, washed sequentially with saturated ammonium chloride solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford an oil. Column chromatography of the oil using silica gel and methylene chloride / hexane solution (1: 1) gave the title compound as a yellow oil, which was confirmed by 1 H NMR spectral analysis. [248] Example 16 [249] Preparation of 6-fluoro-3-methyl-5-nitro-1,2-benzisoxazole [250] [251] A mixture of 6-fluoro-3-methyl-1,2-benzisoxazole (23.5 g, 0.156 mmol) in concentrated sulfuric acid is cooled in an ice bath and maintained at 90% nitric acid (while maintaining the temperature of the reaction mixture below 15 ° C). 8.50 ml) was added dropwise, stirred for 1 hour at ice bath temperature, treated with additional 90% nitric acid (5.80 ml), warmed to room temperature and stirred at room temperature overnight, poured onto ice. The resulting aqueous mixture was filtered to give a solid. The solid was air dried and dissolved in methylene chloride. The resulting organic solution was dried over anhydrous magnesium sulfate, diluted with hexanes and filtered to yield the title compound as a purple solid, which was confirmed by 1 H NMR analysis. [252] Using the same method, the following compounds were obtained: [253] [254] Example 17 [255] Preparation of methyl [(5-nitro-1,2-benzisoxazol-3-yl) oxy] acetate [256] [257] A mixture of 5-nitro-1,2-benzisoxazol-3-ol (3.90 g, 0.0220 mol) and potassium carbonate (4.17 g, 0.0300 mol) in N, N-dimethylformamide was stirred for 30 minutes, methyl Treated with bromoacetate (3.96 g, 0.0260 mol), stirred overnight at room temperature and poured into an acidic ice-water mixture. The resulting aqueous mixture was extracted with ethyl acetate. The organic extracts were combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford a yellow oil. Column chromatography using silica gel and (1: 1) to (4: 1) methylene chloride / hexane gradient gave the title compound as a white solid (2.80 g, mp 72-73.5 ° C), which was subjected to NMR spectral analysis. It confirmed by. [258] Using the same method, the following compounds were obtained: [259] [260] Example 18 [261] Preparation of 3-chloro-5-nitro-1,2-benzisoxazole [262] [263] 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) was placed in a glass spring and 2 at 150-155 ° C. Heated for hours, cooled overnight, concentrated in vacuo, diluted with methylene chloride and adjusted to about pH 8 with sodium hydrogen carbonate solution. The phases were separated. The organic phase was washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford a residue. Column chromatography of the residue with silica gel and methylene chloride / hexane solution (1: 1) gave the title compound as an amber oil, which was confirmed by NMR spectral analysis. [264] Example 19 [265] Preparation of 2-chloro-2'-methoxy-5-nitrobenzophenone [266] [267] A solution of 2-bromoanisole (27.9 g, 145 mmol) in diethyl ether was cooled to -70 ° C, treated with butyllithium (64.0 mL, 160 mmol), stirred at -70 ° C for 1 hour, Treated with a 0.5 M solution of zinc chloride in tetrahydrofuran (320 mL, 160 mmol), stirred at −70 ° C. for 1 hour, warmed to about 0 ° C. and concentrated in vacuo to give a yellowish green oil. A solution of this oil in tetrahydrofuran was converted to tetrakis (triphenylphosphine) palladium (0) (5.00 g, 4.35 mmol), and 2-chloro-5-nitrobenzoyl chloride (35.0 g, 159 mmol) in tetrahydrofuran. Treated sequentially with a solution of, stirred for 3 days and poured into 10% hydrochloric acid. The resulting aqueous mixture was extracted with methylene chloride. The organic extracts were combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a semisolid. The solid was triturated with diethyl ether to give the title compound as a yellow solid, which was confirmed by NMR spectral analysis. [268] Using the same method, the following compounds were obtained: [269] [270] Example 20 [271] Preparation of 2-chloro-2'-methoxy-5-nitrobenzhydrol [272] [273] A solution of 2-bromoanisole (50.0 g, 0.267 mol) in ether was added portionwise to a mixture of magnesium (7.10 g, 0.293 mol) in ether. After the addition was complete, the reaction mixture was heated to reflux for 1 hour, diluted with ether, cooled to 0 ° C. and treated with a solution of 2-chloro-5-nitrobenzaldehyde (39.0 g, 0.210 mol) in tetrahydrofuran. Warmed to room temperature and diluted with ice-water mixture. After the aqueous mixture was acidified with hydrochloric acid (pH 2-pH 3), the organic phase was separated and the aqueous phase was extracted with ether. The organic extracts were combined, washed sequentially with 10% sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound as a brown gum. [274] Using the same method, the following compounds were obtained: [275] [276] Example 21 [277] Preparation of 2-chloro-2'-methoxy-5-nitrobenzophenone [278] [279] A solution of chromium (VI) (91.0 g, 0.919 mol) in water / acetic acid solution (1: 4) was added 2-chloro-2'-methoxy-5-nitro while maintaining the reaction mixture temperature between 25 ° C and 35 ° C. To the benzhydrol (64.2 g, 0.219 mol) was added in portions. The reaction mixture was then stirred at 25 ° C. to 35 ° C. for 1 hour, cooled, diluted with water and concentrated in vacuo to afford a residue. This residue was diluted with water and extracted with methylene chloride. The organic extracts were combined, dried over anhydrous sodium sulfate, mixed with silica gel (10 g) and filtered. The filtrate was concentrated in vacuo to give an oil. The solution of the oil in a methanol / water solution was decolorized with charcoal and concentrated in vacuo to give a residue. Column chromatography of the residue with silica gel and methylene chloride / hexane solution gave the title compound as a white solid. [280] Using the same method, the following compounds were obtained: [281] [282] Example 22 [283] Preparation of 2-chloro-4-fluoro-5-nitrobenzoyl chloride [284] [285] A mixture of 2-chloro-4-fluoro-5-nitrobenzoic acid (50.0 g, 0.228 mol) and N, N-dimethylformamide (5 drops) in 1,2-dichloroethane was added to oxalyl chloride (30.8 mL, 0.353 mol). ) Was added dropwise, refluxed for 3 hours, cooled and concentrated in vacuo to afford the title compound as an orange solid, which was confirmed by NMR spectral analysis. [286] Following almost the same method, 2,4-difluoro-5-nitrobenzoylchloride was obtained as a brown oil using 2,4-difluoro-5-nitrobenzoic acid. [287] Example 23 [288] Preparation of 2'-Chloro-4'-fluoro-5'-nitroaceto-phenone [289] [290] A 2 M solution of methyl zinc chloride in tetrahydrofuran (5.00 mL, 10.1 mmol) was treated dropwise with a solution of 2-chloro-4-fluoro-5-nitrobenzoyl chloride (2.00 g, 8.40 mmol) in tetrahydrofuran. Tetrakis (triphenylphosphine) palladium (0) [291] (0.400 g, 0.350 mmol), stirred at rt for 1 h and poured into 3 N hydrochloric acid. The resulting aqueous mixture was extracted with ethyl acetate. The organic extracts were combined, washed sequentially with water and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a dark liquid. Flash column chromatography of the liquid with silica gel and a solution of methylene chloride in hexanes (6: 4) gave the title compound as an off-white solid (mp 66-68 ° C.), which was confirmed by NMR spectral analysis. [292] Example 24 [293] Preparation of 6-amino-3-methyl-5-nitro-1,2-benzisothiazole [294] [295] Of 2'-chloro-4'-fluoro-5'-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 The mixture is placed in a steel spring, heated at 85 ° C. overnight, cooled, treated with additional sulfur (0.270 g) and 30% ammonium hydroxide solution (50 mL), heated at 85 ° C. overnight, cooled and filtered The solid was removed and extracted with ethyl acetate. The organic extracts were combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a solid. Flash column chromatography of the solid with silica gel and 0%, 1% and 2% diethyl ether solutions in methylene chloride gave the title compound as an orange solid (4.19 g, mp 189-191 ° C), which was subjected to NMR. Confirmed by spectral analysis. [296] Nearly the same method was used to obtain the following compounds: [297] [298] Example 25 [299] Preparation of 6-chloro-3-methyl-5-nitro-1,2-benzisothiazole [300] [301] A mixture of t-butyl nitrate (3.30 mL, 0.0278 mol) and copper (II) chloride (2.98 g, 0.0222 mol) in acetonitrile was heated to 65 ° C. and 6-amino-3-methyl-5-nitro-1 Treated slowly with, 2-benzisothiazole (3.88 g, 0.0185 mol), stirred at 65 ° C., cooled to room temperature and poured into 20% hydrochloric acid. The resulting aqueous mixture was extracted with ethyl acetate. The organic extracts were combined, washed with 20% hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a solid. Flash column chromatography of the solid with silica gel and methylene chloride / hexane solution (1: 1 and 3: 1) gave the title compound as a light yellow solid (2.54 g, mp 156-158 ° C), which was analyzed by NMR spectrum. Confirmed by analysis. [302] Nearly the same method was used to obtain the following compounds: [303] [304] Example 26 [305] Preparation of 6-fluoro-3-methyl-5-nitro-1,2-benzisothiazole [306] [307] 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) in acetonitrile g, 5.70 mmol) was heated in a sealed tube for 29 days, filtered to remove the solid, and partially concentrated in vacuo to give a solid. This solid was diluted with ethyl acetate, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford a dark brown solid. Flash column chromatography of the solid using silica gel and 10% to 50% ethyl acetate gradient in hexanes gave a yellow solid containing two components. Flash column chromatography of the yellow solid using 50% to 70% methylene chloride gradient in silica gel and hexane gave the title compound as a light yellow solid (0.870 g, mp 118-119 ° C.), which was analyzed by NMR spectral analysis. Confirmed. [308] Nearly the same method was used to obtain the following compounds: [309] [310] Example 27 [311] Preparation of 2,2'-dithiobis [5-nitrobenzoic acid] [312] [313] A mixture of 2-chloro-5-nitrobenzoic acid (100 g, 0.496 mol) in ethanol was treated with potassium t-butoxide (55.5 g, 0.495 mol) in portions, diluted with additional ethanol, heated to reflux and sulfided Treated little by little with a solution prepared from sodium chydrate (60.0 g, 0.249 mol), sulfur (8.80 g, 0.274 mol) and water, refluxed for 2 hours, cooled to room temperature and treated with concentrated hydrochloric acid. The resulting acid mixture was stirred for 1 hour and filtered to give a solid. This solid was washed with water and air dried to afford the title compound as a yellow powder which was confirmed by NMR spectral analysis. [314] Example 28 [315] Preparation of 5-nitro-1,2-benzisothiazol-3 (2H) -one [316] [317] Treatment of 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 with N, N-dimethylformamide (0.800 mL) It was refluxed overnight, concentrated in vacuo and diluted with 1,2-dichloroethane. The resulting organic solution was treated with bromine (22.5 mL, 0.436 mol), stirred at rt for 20 min, refluxed for 3.5 h and concentrated in vacuo to afford a residue. The 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 concentrated with hydrochloric acid. Treated. The resulting aqueous mixture was stirred at rt for 1 h and filtered to give a solid. This solid was washed with water and air dried to afford the title compound as a yellow solid, which was confirmed by NMR spectral analysis. [318] Example 29 [319] Preparation of 3-chloro-5-nitro-1,2-benzisothiazole [320] [321] 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) Was heated at 103-115 ° C. for 6 h, stirred at rt overnight, and poured into an ice-water mixture. The resulting aqueous mixture was extracted with methylene chloride. The combined organic extracts were washed sequentially with water and saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give a gum. Column chromatography of the gum with silica gel and methylene chloride gave the title compound as an orangeish yellow solid, which was confirmed by NMR spectral analysis. [322] Example 30 [323] Preparation of ethyl α-cyano-5-nitro-1,2-benzisothiazole-3-acetate [324] [325] Sodium ethoxide solution (previously prepared from ethanol and sodium (1.00 g, 0.0430 mol)) is cooled in an ice-acetone bath, treated slightly with ethyl cyanoacetate (4.51 g, 0.0398 mol) and 30 minutes at room temperature. Stirred for 3 hours, treated gradually with 3-chloro-5-nitro-1,2-benzisothiazole (4.27 g, 0.0199 mol), stirred overnight at room temperature, cooled to 0 ° C., 10% hydrochloric acid (15.0 mL ) Was added dropwise. The resulting aqueous mixture was stirred at rt for 1 h and filtered to give a solid. This solid was washed with ethanol and air dried to afford the title compound as a yellow solid, which was confirmed by NMR spectral analysis. [326] Example 31 [327] Preparation of ethyl 5-nitro-1,2-benzisothiazole-3-acetate [328] [329] Ethyl α-cyano-5-nitro-1,2-benzisothiazole-3-acetate (6.67 g, 0.0229 mol) was added to a solution of acetyl chloride (67.0 mL) in ethanol. The reaction mixture was refluxed overnight, cooled and filtered to remove solids. The resulting filtrate was concentrated in vacuo to give a brown semisolid. The mixture of the semisolid in diethyl ether was stirred for 2 hours and filtered to give a solid. This solid was washed with diethyl ether and air dried to give the title compound as yellow crystals (1.04 g, mp 91-92 ° C.). [330] Example 32 [331] Preparation of 5-nitro-1,2-benzisothiazole-3-aceto-nitrile [332] [333] A mixture of ethyl 5-nitro-1,2-benzisothiazole-3-acetate (5.00 g, 17.2 mmol), water (1.00 mL), and methyl sulfoxide (35.0 mL) was stirred at 107 ° C. for 24 hours and , Stirred for 2 days at room temperature and poured into an ice-water mixture. The resulting aqueous mixture was stirred for 2 hours and filtered to give a solid. This solid was washed with water and air dried to afford the title compound as a tan solid. [334] Example 33 [335] Preparation of α, α-dimethyl-5-nitro-1,2-benzisothiazole-3-acetonitrile [336] [337] A mixture of 5-nitro-1,2-benzisothiazole-3-aceto-nitrile (1.29 g, 5.89 mmol) in N, N-dimethylformamide was cooled to -9 ° C and sodium hydride (60% in oil) 1.00 g) of the dispersion), stirred at −3 ° C. for 20 min, treated with iodomethane (5.00 mL), stirred at rt for 4 h and poured onto ice. The resulting aqueous mixture was treated with 10% hydrochloric acid and extracted with methylene chloride. The combined organic extracts were washed sequentially with water, saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and concentrated in vacuo to give a solid. Column chromatography with silica gel and methylene chloride gave the title compound as a yellow solid, which was confirmed by NMR spectral analysis. [338] Example 34 [339] Preparation of ethyl α, α-dimethyl-5-nitro-1,2-benzisothiazole-3-acetate [340] [341] α, α-dimethyl-5-nitro-1,2-benzisothiazole-3-acetonitrile (0.913 g, 3.69 mmol), water (0.450 mL), concentrated sulfuric acid (4.55 mL) and ethanol (9.10 mL) The mixture was refluxed for 1 hour, cooled and poured onto ice. The resulting aqueous mixture was neutralized with saturated sodium bicarbonate solution and extracted with methylene chloride. The organic extract was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to give a solid. Column chromatography of the solid with silica gel and methylene chloride gave the title compound as pale yellow crystals. Confirmed by spectral analysis. [342] Example 35 [343] Preparation of 5-amino-3-chloro-1,2-benzisothiazole [344] [345] A solution of 3-chloro-5-nitro-1,2-benzisothiazole (2.00 g) in toluene was treated with iron powder (8.40 g, 325 mesh) and concentrated hydrochloric acid (8 drops) and heated to reflux, Water (8.00 mL) was added dropwise, treated at reflux for 35 minutes, cooled to room temperature and filtered through diatomaceous earth. The resulting filtrate was concentrated in vacuo to give a residue. The title compound was obtained via flash column chromatography of the residue using silica gel and ethyl acetate / hexane solution (1: 1). [346] Example 36 [347] Preparation of [(5-nitro-1,2-benzisothiazol-3-yl) -oxy] acetonitrile [348] [349] A mixture of 5-nitro-1,2-benzisothiazol-3 (2H) -one (17.5 g, 89.2 mmol) in N, N-dimethylformamide was treated with potassium carbonate (18.5 g, 134 mmol), Stir at room temperature for 30 minutes, treat with bromoacetonitrile (16.0 g, 133 mmol), stir overnight at room temperature and pour over ice. The resulting aqueous mixture was acidified to pH 3 with hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a solid. Column chromatography of the solid using silica gel and methylene chloride gave the title compound as a yellow solid (15.0 g, mp 123-124.5 ° C.). [350] Using the same method, the following compounds were obtained: [351] [352] [353] Example 37 [354] Preparation of 5-nitro-1,2-benzisothiazole [355] [356] In a mixture of ammonium hydroxide (1000 ml) and N, N-dimethylformamide 2-chloro-5-nitrobenzaldehyde (300 g, 1.62 mol) and sulfur (54.4 g, 1.70 mol) were added. The mixture was slowly heated to 90 ° C. and stirred at 90 ° C. for 1 hour, cooled to room temperature, poured over ice and diluted with water. Filtration gave the title compound as a yellow solid (277.1 g, 94.9%). [357] Ethyl-α, α-dimethyl-5-nitro- was used in substantially the same manner except that 2'-chloro-5'-nitro-2-methyl-2-carboethoxypropiophenone was used. 1,2-benzisothiazole-3-acetate was obtained as a solid (mp 75-77 ° C.). [358] Example 38 [359] Preparation of 3-chloro-5-nitro-1,2-benzisothiazole [360] [361] A suspension of 5-nitro-1,2-benzisothiazole (271 g, 1.50 mol) in acetic acid was heated to 80 ° C. to form a solution. The heat source was removed and chlorine gas was added continuously at 70-80 ° C. over 6 hours until saturation of the mixture occurred. The mixture was cooled to room temperature and stirred overnight. Filtration gave the title compound as a yellow crystal solid (237 g, 73.6%), which was confirmed by NMR spectral analysis. [362] Example 39 [363] Preparation of 2'-chloro-2-methyl-2-carboethoxy propiophenone [364] [365] A mixture of 2-chlorobenzoyl chloride (52.2 g, 0.298 mol), ethyl 2-bromoisobutyrate (58.2 g, 0.298 mol) and ether was added in small portions to zinc foil (19.5 g, 0.298 mol) and the resultant The mixture was stirred at reflux for 3 hours and at room temperature overnight. The mixture was poured into cold diluted sulfuric acid, and the organic layer was washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a yellow oil. This oil was chromatographed on silica gel with hexanes: ethyl acetate to afford the title compound as a colorless oil (41.8 g, 55.1%). [366] Example 40 [367] Preparation of 2'-chloro-5'-nitro-2-methyl-2-carboethoxypropiophenone [368] [369] To 5 ° C. concentrated sulfuric acid (15.0 mL) was added 2'-chloro-2-methyl-2-carboethoxypropiophenone (4.00 g, 0.01570 mol), followed by concentrated nitric acid (90%, 0.740 ml, 0.0204). mol) was added dropwise. After stirring for 5 minutes, the mixture was poured onto ice and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as a yellow oil (3.90 g, 83.0%), which was confirmed by NMR spectral analysis. [370] Example 41 [371] Preparation of 1-benzothiophene-2,3-dione [372] [373] To a solution of thiophenol (100 g, 0.907 mol) in ether was added dropwise a solution of oxalyl chloride (175 g, 1.38 mol) in ether. The mixture was stirred at reflux for 2 hours and concentrated in vacuo. The residue was dissolved in methylene chloride and cooled to 0 ° C. Aluminum chloride (145 g, 1.09 mol) was added little by little so that temperature did not exceed 25 degreeC. The resulting mixture was stirred at reflux for 30 minutes, cooled to room temperature and poured into ice water with stirring. The organic layer was washed with saturated sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give an orange solid, recrystallized from methylene chloride: hexane to give the title compound (102 g, 69.0%). This was confirmed by NMR spectral analysis. [374] Example 42 [375] Preparation of 1,2-benzisothiazole-3-carboxamide [376] [377] 1-benzothiophene-2,3-dione (87.0 g, 0.530 mol) was added to ammonium hydroxide (1.78 L) at 5-10 ° C., followed by hydrogen peroxide (30% aqueous solution, 178 ml). The resulting mixture was filtered to give a yellow solid which was dried (77.0 g, 81.7%) and the title compound was confirmed by NMR and IR spectral analysis. [378] Example 43 [379] Preparation of 3-cyano-5-nitro-1,2-benzisothiazole [380] [381] To a solution of 1,2-benzisothiazole-3-carboxamide (12.0 g, 0.0674 mol) in concentrated sulfuric acid at 0-5 ° C. was added dropwise nitric acid (90%, 4.12 ml) so that the temperature did not exceed 10 ° C. Treated, stirred at 5 ° C. for 1 h and poured into ice water with vigorous stirring. The resulting suspension was filtered to give a solid. This solid was dried and recrystallized from acetonitrile to give a white solid (10.0 g) which was treated with phosphorus oxychloride (60.0 ml). The resulting mixture was stirred at 90-100 ° C. for 90 minutes, cooled to room temperature, slowly poured into ice water with stirring and filtered to give a solid. This solid was recrystallized from methylene chloride: hexane to give the title compound as an orange solid (8.00 g, 87.9%, mp 168-170 ° C.) which was confirmed by NMR and IR spectral analysis. [382] Example 44 [383] Preparation of 3- (6-methoxy-m-tolyl) -6-amino-5-nitro-1,2-benzisothiazole [384] [385] Ammonium hydroxide (330 ml) was added to 2 ', 4'-difluoro-2-methoxy-5-methyl-5'-nitrobenzophenone (60.0 g, 0.186 mol), sulfur (6.25 g, 0.195 mol) on an ice bath. ) And a suspension of N, N-dimethylformamide. The resulting mixture was warmed to 35 ° C., heated gradually to 81 ° C. over 2 hours, cooled to room temperature and poured into water. The resulting solid was dissolved in ethyl acetate and N, N-dimethylformamide and washed with water. The organic layer was concentrated in vacuo to afford the title compound, which was confirmed by NMR spectral analysis. [386] Example 45 [387] Preparation of 3- (6-methoxy-m-tolyl) -6-chloro-5-nitro-1,2-benzisothiazole [388] [389] A mixture of t-butyl nitrite (5.90 g, 0.0571 mol), copper chloride (6.20 g, 0.0457 mol) and acetonitrile was heated to 65-75 ° C. and 3- (6-methoxy-m- over 10 minutes. Treated with tolyl) -6-amino-5-nitro-1,2-benzisothiazole (12.0 g, 0.0381 mol), treated with t-butyl nitrite (1.50 ml) and copper chloride (1.00 g), Stir for 40 min at 67-75 ° C and dilute with ethyl acetate. The organic layer was washed with 10% hydrochloric acid and filtered. The filtrate was washed with water and concentrated in vacuo to afford the title compound as a solid (10.6 g, 83.1%), which was confirmed by NMR and IR spectral analysis. [390] Example 46 [391] Preparation of 3- (6-methoxy-m-tolyl) -6-fluoro-5-nitro-1,2-benzisothiazole [392] [393] 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- The mixture of Crown-6 (2.31 g, 0.0872 mol) and sulfolane was stirred at 154 ° C. for 19 hours, cooled to room temperature and poured into ice water. The resulting solid was filtered and chromatographed with methylene chloride on silica gel to give a solid which was recrystallized from acetonitrile to give a tan powder. This powder was recrystallized from ethyl acetate to give the title compound as a yellow-yellow solid (2.09 g, 29.9%), which was confirmed by NMR spectral analysis. [394] Example 47 [395] Preparation of 5-amino-4-bromo-6-fluoro-3-methyl-1,2-benzisothiazole [396] [397] N-bromosuccinimide (0.586 g, 0.00329) in a solution of 5-amino-6-fluoro-3-methyl-1,2-benzisothiazole (0.600 g, 0.00329 mol) in 1,2-dichloroethane mol), then 1,1'-azobis (cyclohexanecarbonitrile) (0.0200 g) was added. The mixture was stirred at 70 ° C. for 2 hours, additional N-bromosuccinimide (0.240 g, 0.00135 mol) was added and the mixture was stirred at 70 ° C. for 40 minutes. The mixture was then cooled to room temperature, filtered and concentrated in vacuo to give a residue. This residue was chromatographed on silica gel to give the title compound (0.870 g, 100%) which was confirmed by NMR spectral analysis.
权利要求:
Claims (11) [1" claim-type="Currently amended] (a) reacting a carbamate compound of formula II with an amine compound of formula III in the presence of a base to yield 6- (perfluoroalkyl of formula I, wherein Y is hydrogen or C 1 -C 6 alkyl To produce uracil compounds, (b) optionally alkylating a compound of formula I wherein Y is hydrogen to form a compound of formula I wherein Y is C 1 -C 4 alkyl A process for preparing a 6- (perfluoroalkyl) uracil compound of formula I, comprising: <Formula I> (Wherein n is an integer of 1, 2, 3, 4, 5 or 6; Y is hydrogen or C 1 -C 6 alkyl; Q is a C 1 -C 6 alkyl group or an optionally substituted phenyl, benzyl, heteroaryl or methyleneheteroaryl group) <Formula II> Wherein Z and Z 1 are each independently C 1 -C 6 alkyl, or the phenyl ring is optionally selected from any combination of 1 to 3 halogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl groups Substituted benzyl; n and Y are as mentioned above) <Formula III> QNH 2 (Wherein Q is as mentioned above) [2" claim-type="Currently amended] The method of claim 1 wherein the double bond in the compound of Formula II is predominantly (Z) -configuration. [3" claim-type="Currently amended] The method of claim 1 wherein the base is selected from the group consisting of tri (C 1 -C 6 alkyl) amines, heterocyclic tertiary amines and alkali metal C 1 -C 6 alkoxides. [4" claim-type="Currently amended] 4. The base of claim 3 wherein the base is selected from the group consisting of 1,8-diazabicyclo [5.4.0] undec-7-ene and 1,5-diazabicyclo [4.3.0] non-5-ene How to be. [5" claim-type="Currently amended] The method of claim 1 wherein the carbamate compound and the amine compound are reacted in the presence of a solvent. [6" claim-type="Currently amended] The process of claim 5 wherein the solvent is selected from the group consisting of carboxylic acid amides, dialkyl sulfoxides, aromatic hydrocarbons, halogenated aromatic hydrocarbons, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, alcohols, ketones, ethers, nitriles and water and mixtures thereof. How. [7" claim-type="Currently amended] The method of claim 1 wherein the carbamate compound, the amine compound, and the base are reacted at a temperature of about 20 ° C. to 150 ° C. 7. [8" claim-type="Currently amended] The process of claim 1, wherein step (b) comprises reacting a compound of formula (I) wherein Y is hydrogen in the presence of a base with an alkyl halide of formula (IV) or a dialkylsulfate ester of formula (V). <Formula IV> XY <Formula V> Wherein X is chlorine, bromine or iodine and Y is C 1 -C 6 alkyl. [9" claim-type="Currently amended] The method of claim 1, n is 1; Y is hydrogen or C 1 -C 4 alkyl; Q is ego; G is CH 2 or a bond; G 1 is CX 5 or N; G 2 is CX 4 or N; X 1 is hydrogen, halogen or a C 1 -C 6 alkyl group optionally substituted with one epoxy group, X 2 is hydrogen, halogen, NRR 1 , CO 2 R 2 , C (O) R 3 , OR 4 , SO 2 R 5 , SO 2 NR 6 R 7 , C (R 8 ) (OR 9 ) 2 , C ( R 10 ) = NOR 11 , C (R 12 ) = C (R 13 ) -C (OR 14 ) = NOR 15 , CH 2 O—NCO 2 R 16 , optionally one C 1 -C 6 alkoxy group or one or 1,3-dioxolane substituted with two C 1 -C 4 alkyl groups, 1,3-dioxolinone optionally substituted with one C 1 -C 6 alkoxy group or one or two C 1 -C 4 alkyl groups, Or C 1 -C 4 alkyl optionally substituted with one CO 2 R 2 group and one halogen atom, X 3 is hydrogen, halogen, C 1 -C 4 haloalkyl, CO 2 R 17 , cyano, C 1 -C 4 haloalkoxy, OR 18 or C 1 -C 4 alkyl, or X 1 and X 2 together with the atoms to which they are attached, X 1 X 2 or X 2 X 1 represents —OC (R 20 ) (R 21 ) O—, —CHS (O) p N (R 22 ) —, -SC (R 23 ) = N-, -CH = CH-CH (R 11 ) O-, -OC (O) N-, -SC (R 24 ) = N-, -ON (R 25 ) C (O )-, -OC (CO 2 R 26 ) = C (R 27 )-, -NC (R 28 ) = C (SR 29 )-, -CH = C (CO 2 R 30 ) O-, -CH 2 CH May form a 5-6 membered ring represented by (R 31 ) O— or —OC (R 32 ) (R 33 ) C (O) —, or X 2 and X 3 together with the atoms to which they are attached, X 2 X 3 or X 3 X 2 is -NC (R 34 ) = NC (S)-, -N (R 35 ) N = C (R 36 ) -, -N (R 37 ) C (R 38 ) = N-, -N (R 38 ) C (O) CH 2 O-, -N (R 39 ) C (O) CH = CH-, -SN = C (R 40 )-, -ON = C (R 41 )-, -N = NN (R 42 )-, -C (R 43 ) (R 44 ) C (O) N (R 45 )-or -N May form a 5- to 6-membered ring represented by (R 46 ) C (O) C (R 47 ) (R 48 )-; X 4 is hydrogen, halogen or OR 19 ; X 5 is hydrogen or halogen; R, R 56 , R 64 , R 69 , R 70 , R 77 and R 91 are each independently hydrogen, SO 2 R 49 , C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 6 Alkenyl, C 3 -C 6 alkynyl, phenyl or benzyl; R 1 is hydrogen, SO 2 R 50 , C (O) R 51 , amino or C 1 -C 4 alkyl optionally substituted with CO 2 R 52 or C (O) R 53 ; R 2 , R 16 , R 17 , R 26 , R 30 , R 68 , R 75 , R 76 , R 82 and R 88 are each independently hydrogen, C 1 -C 8 haloalkyl, C 3 -C 8 alkenyl , C 3 -C 6 alkynyl, phenyl, benzyl, furfuryl, pyridyl, thienyl, C 1 -C 8 alkyl optionally substituted with CO 2 R 54 , morpholine or C (O) R 55 , or an alkali metal , Alkaline earth metal, ammonium or organic ammonium cations; R 3 , R 66 , R 67 , R 81 , R 85 and R 89 are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, NR 56 R 57 , Phenyl or benzyl; R 4 , R 18 , R 19 and R 65 are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 1 -C 4 haloalkyl, C ( O) R 58 , C (S) R 59 or benzyl; R 5 and R 72 are each independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, NR 60 R 61 , imidazole or indazole; R 6 , R 11 , R 12 , R 14 , R 15 , R 20 , R 21 , R 22 , R 25 , R 28 , R 29 , R 31 , R 32 , R 33 , R 35 , R 45 , R 46 , R 63 and R 80 are each independently hydrogen or C 1 -C 4 alkyl; R 7 is hydrogen, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, benzyl, or C 1 -C 4 alkyl optionally substituted with cyano or C (O) R 62 ; R 8 and R 27 are each independently hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; R 9 and R 90 are each independently C 1 -C 6 alkyl; R 10 is hydrogen, C 1 -C 6 alkyl, phenyl or benzyl; R 13 , R 24 and R 36 are each independently hydrogen, C 1 -C 6 alkyl or halogen; R 23 is hydrogen or NR 63 R 64 ; R 34 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; R 37 is hydrogen, C 1 -C 4 alkyl or C 2 -C 8 alkoxyalkyl; R 38 and R 39 are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 alkenyl or C 3 -C 6 alkynyl; R 40 , R 41 and R 42 are each independently hydrogen, halogen, cyano, OR 65 , C (O) R 66 , C (S) R 67 , CO 2 R 68 , C (= NOR 69 ), C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl group, wherein C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl groups each have 1 to 6 halogen atoms, 1 to 3 C 1 -C 10 alkoxy groups, one or two C 1 -C 6 haloalkoxy groups, one or two NR 70 R 71 groups, one or two S (O) q R 72 groups, one or two cyano groups, one or two C 3 -C 7 cycloalkyl groups, one OSO 2 R 73 group, one or two C (O) R 74 groups, one or two CO 2 R 75 groups, one or two C (O) SR 76 groups, one or two C (O) NR 77 R 78 groups, one to three OR 79 groups , one or two P (O) (oR 80) 2 group, optionally one of the 1, 3-dioxolanyl optionally substituted with one to three C 1 -C 4 alkyl group solran, Optionally one or any combination of a single 1,3-dioxane substituted with three C 1 -C 4 alkyl groups also being optionally substituted), or phenyl or benzyl (wherein the phenyl or benzyl are one to three halogen atoms , One to three C 1 -C 6 alkyl groups, one to three C 1 -C 6 alkoxy groups, one C 3 -C 7 cycloalkyl group, one C 1 -C 4 haloalkyl group, one C 1 -C 4 alkylthio groups, one cyano group, one nitro group, one C (O) R 81 group, one CO 2 R 82 group, one OR 83 group, one SR 84 group, one C 1- Optionally substituted with any combination of a C 6 alkoxymethyl group, one hydroxymethyl group, one C 3 -C 8 alkenyloxymethyl group, or one C 1 -C 8 haloalkoxymethyl group; R 43 , R 44 , R 47 and R 48 are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl or C 3 -C 7 cycloalkyl, or R 43 and R 44 or R 47 and R 48 together with the atoms to which they are attached may form a C 3 -C 7 cycloalkyl group; R 49 , R 50 and R 86 are each independently C 1 -C 6 alkyl, NR 93 R 94 , C 1 -C 4 haloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl or benzyl ; R 51 , R 52 , R 53 , R 54 , R 55 , R 57 , R 58 , R 59 , R 60 , R 61 , R 62 , R 71 , R 73 , R 74 , R 78 , R 87 and R 92 Are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, phenyl or benzyl; R 79 , R 83 and R 84 are each independently hydrogen, C (O) R 85 , SO 2 R 86 , C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 5 -C 8 cycloalkenyl , C 2 -C 6 alkynyl, phenyl, benzyl, or C 1 -C 10 alkyl (C 1 -C 10 alkyl is one hydroxyl, benzyloxy, OC (O) R 87 , C 1 -C 6 alkoxy, Optionally substituted with C0 2 R 88 , C (O) R 89 , C (OR 90 ) 2 , C (0) NR 91 R 92 or cyano group; R 93 and R 94 are each independently hydrogen, C 1 -C 4 haloalkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkyl, wherein C 1 -C 8 alkyl Is optionally substituted with one or two C 1 -C 4 alkoxy groups or one cyanoalkyl group, or benzyl or phenyl, wherein benzyl or phenyl is one to three halogen atoms, one to three C 1 -C Of 4 alkyl groups, one to three C 1 -C 4 haloalkyl groups, one to three C 1 -C 4 alkoxy groups, one to three C 1 -C 4 haloalkoxy groups, one cyano group or one nitro group Optionally substituted in any combination) or R 93 and R 94 are 5- to 12-membered monocyclic or fused bicyclic heterocyclic rings together with the atoms to which they are attached, wherein the heterocyclic ring is halogen , Cyano, nitro, amino, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and to form a C 1 -C 4 haloalkyl being independently optionally substituted with one or more groups selected from alkyl sulfonyl group); p and q are each independently 0, 1 or 2; Z and Z 1 are each independently C 1 -C 4 alkyl. [10" claim-type="Currently amended] The method of claim 9, Y is hydrogen or methyl; X 1 is hydrogen, fluorine or C 1 -C 3 alkyl optionally substituted with one epoxy group; X 2 is hydrogen, halogen, NRR 1 , CO 2 R 2 , C (O) R 3 , OR 4 , SO 2 R 5 , SO 2 NR 6 R 7 , C (R 8 ) (OR 9 ) 2 , C ( R 10 ) = NOR 11 , C (R 12 ) = C (R 13 ) -C (OR 14 ) = NOR 15 , CH 2 O—NCO 2 R 16 , optionally one C 1 -C 6 alkoxy group or one or 1,3-dioxolane substituted with two C 1 -C 4 alkyl groups, 1,3-dioxolinone optionally substituted with one C 1 -C 6 alkoxy group or one or two C 1 -C 4 alkyl groups, Or C 1 -C 4 alkyl optionally substituted with one CO 2 R 2 group and one halogen atom, X 3 is hydrogen, halogen, C 1 -C 4 haloalkyl, CO 2 R 17 , cyano, C 1 -C 4 haloalkoxy, OR 18 or C 1 -C 4 alkyl, or X 1 and X 2 together with the atoms to which they are attached, X 1 X 2 or X 2 X 1 is —OC (R 20 ) (R 21 ) O—, —CH 2 S (O) p N (R 22 ) -, -SC (R 23 ) = N-, -CH = CH-CH (R 11 ) O-, -OC (O) N-, -SC (R 24 ) = N-, -ON (R 25 ) C (O)-, -OC (CO 2 R 26 ) = CH-, -NC (R 28 ) = C (SR 29 )-, -CH = C (CO 2 R 30 ) O-, -CH 2 CH (R 31 ) may form a 5- or 6-membered ring represented by O- or -OC (R 32 ) (R 33 ) C (O)-, or X 2 and X 3 together with the atoms to which they are attached, X 2 X 3 or X 3 X 2 is -NC (R 34 ) = NC (S)-, -N (R 35 ) N = C (R 36 ) -, -N (R 37 ) C (R 38 ) = N-, -N (R 38 ) C (O) CH 2 O-, -N (R 39 ) C (O) CH = CH-, -SN = C (R 40 )-, -ON = C (R 41 )-, -N = NN (R 42 )-, -C (R 43 ) (R 44 ) C (O) N (R 45 )-or May form a 5- or 6-membered ring represented by -N (R 46 ) C (O) C (R 47 ) (R 48 )-; X 4 is hydrogen, halogen or OR 19 ; X 5 is hydrogen or halogen; R, R 64 , R 69 , and R 77 are each independently hydrogen, SO 2 R 49 , or C 1 -C 4 alkyl; R 1 is hydrogen, SO 2 R 50 , C (O) R 51 , amino, or C 1 -C 4 alkyl optionally substituted with CO 2 R 52 or C (O) R 53 ; R 2 , R 16 , R 17 , R 26 , R 30 , R 68 , R 75 , R 76 , R 82 and R 88 are each independently hydrogen, C 3 -C 6 alkenyl, or optionally CO 2 R 54 , Morpholine or C 1 -C 4 alkyl substituted with C (O) R 55 ; R 3 , R 66 , R 67 , R 85 and R 89 are each independently hydrogen, C 1 -C 4 alkyl or NR 56 R 57 ; R 4 , R 18 and R 19 are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C (O) R 58 , C 3 -C 4 alkenyl or C 3 -C 4 alkoxy Nil; R 56 is SO 2 R 49 ; R 57 is hydrogen or C 1 -C 4 alkyl; R 5 and R 72 are each independently NR 60 R 61 or indazole; R 6 , R 11 , R 12 , R 14 , R 15 , R 20 , R 21 , R 22 , R 25 , R 28 , R 29 , R 31 , R 32 , R 33 , R 35 , R 45 , R 46 And R 80 are each independently hydrogen or methyl; R 7 is cyano or C 1 -C 4 alkyl optionally substituted with C (O) R 62 ; R 8 is hydrogen or C 1 -C 4 alkoxy; R 9 and R 90 are each independently C 1 -C 4 alkyl; R 10 is hydrogen or C 1 -C 4 alkyl; R 13 , R 24 and R 36 are each independently hydrogen or chlorine; R 23 is NR 63 R 64 ; R 34 is C 1 -C 3 haloalkyl; R 37 is C 2 -C 4 alkoxyalkyl; R 38 and R 39 are each independently C 1 -C 3 haloalkyl, C 1 -C 3 alkyl or propargyl; R 40 , R 41 and R 42 are each independently hydrogen, C (O) R 66 , C (S) R 67 , CO 2 R 68 , C (= NOR 69 ), C 1 -C 3 alkyl, wherein C 1- C 3 alkyl is one or two halogen atoms, one or two C 1 -C 3 alkoxy groups, one or two C 1 -C 3 haloalkoxy groups, one S (O) 2 R 72 group, one Or two cyano groups, one C 3 -C 5 cycloalkyl group, one OSO 2 R 73 group, one C (O) R 74 group, one CO 2 R 75 group, one C (O) SR 76 Group, one C (O) NR 77 R 78 group, one or two OR 79 groups, one P (O) (OR 80 ) 2 group, one 1,3-dioxolane, or one 1,3 -Optionally substituted with any combination of dioxane groups), or phenyl, wherein phenyl is optionally substituted with any combination of one halogen atom, one or two methyl groups, one methoxy group, one halomethyl group) ego; R 43 , R 44 , R 47 and R 48 are each independently hydrogen or methyl, or R 43 and R 44 or R 47 and R 48 together with the atoms to which they are attached may form a cyclopropyl group; R 49 , R 50 and R 86 are each independently C 1 -C 4 alkyl or NR 93 R 94 ; R 51 , R 52 , R 53 , R 54 , R 55 , R 58 , R 60 , R 61 , R 62 , R 73 , R 74 , R 78 , and R 87 are each independently hydrogen, C 1 -C 4 Alkyl or C 1 -C 4 haloalkyl; R 79 and R 83 are each independently hydrogen, C (O) R 85 , SO 2 R 86 , C 1 -C 4 haloalkyl, C 3 -C 4 alkenyl, or C 1 -C 3 alkyl (C 1- C 3 alkyl is substituted with one OC (O) R 87 , CO 2 R 88 , C (O) R 89 , C (OR 90 ) 2 or cyano group); R 93 and R 94 are each independently hydrogen or C 1 -C 8 alkyl; p is 0, 1 or 2; Z and Z 1 are each independently a methyl or ethyl group. [11" claim-type="Currently amended] A process for preparing the 6- (trifluoromethyl) uracil compound of formula VI: <Formula VI> Where Y is hydrogen or methyl; X 5 is hydrogen or halogen; R 40 is hydrogen, C (O) R 66 , C (S) R 67 , CO 2 R 68 , C 1 -C 3 alkyl (C 1 -C 3 alkyl is one or two halogen atoms, one or two C 1 -C 3 alkoxy group, one or two C 1 -C 3 haloalkoxy groups, one SO 2 R 72 group, one or two cyano groups, one C 3 -C 5 cycloalkyl group, one OSO 2 R Optionally substituted with any combination of 73 groups, one or two OR 79 groups, one P (O) (OR 80 ) 2 group, one 1,3-dioxolane group or one 1,3-dioxane group Or phenyl (phenyl is optionally substituted with any combination of one halogen atom, one or two methyl groups, one methoxy group, one halomethyl group or one OR 83 group); R 66 , R 67 , R 85 and R 89 are each independently hydrogen, C 1 -C 4 alkyl or NR 56 R 57 ; R 56 is SO 2 R 49 ; R 57 is hydrogen or C 1 -C 4 alkyl; R 49 and R 86 are each independently C 1 -C 4 alkyl or NR 93 R 94 ; R 93 and R 94 are each independently hydrogen or C 1 -C 8 alkyl; R 68 and R 88 are each independently hydrogen, C 3 -C 6 alkenyl or C 1 -C 4 alkyl (C 1 -C 4 alkyl optionally substituted with CO 2 R 54 , morpholine or C (O) R 55 ); R 54 , R 55 , R 60 , R 61 , R 73 and R 87 are each independently hydrogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; R 72 is NR 60 R 61 or indazole; R 79 and R 83 are each independently hydrogen, C (O) R 85 , SO 2 R 86 , C 1 -C 4 haloalkyl, C 3 -C 4 alkenyl, or one OC (O) R 87 , CO 2 R 88 , C (O) R 89 , C (OR 90 ) 2 or C 1 -C 3 alkyl substituted with a cyano group; R 80 is hydrogen or methyl; R 90 is C 1 -C 4 alkyl.
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同族专利:
公开号 | 公开日 BR0008306A|2002-01-22| PL350038A1|2002-10-21| RU2001124594A|2004-02-27| CN1344258A|2002-04-10| CZ20012945A3|2002-04-17| JP4619543B2|2011-01-26| HU0201551A3|2004-03-01| DE60010232D1|2004-06-03| JP2002537290A|2002-11-05| AR022598A1|2002-09-04| EP1150962A1|2001-11-07| EP1150962B1|2004-04-28| AU3364200A|2000-09-04| MXPA01008225A|2003-07-21| CA2362996A1|2000-08-24| HU0201551A2|2002-08-28| DE60010232T2|2004-10-07| IL144834D0|2002-06-30| WO2000049003A1|2000-08-24| AT265440T|2004-05-15|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题
法律状态:
1999-02-16|Priority to US25072599A 1999-02-16|Priority to US09/250,725 2000-02-14|Application filed by 윌리암 에이취 캘넌, 에곤 이 버그, 아메리칸사이아나미드컴파니 2000-02-14|Priority to PCT/US2000/003795 2001-12-31|Publication of KR20010114207A
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