CN1344259A - Processes and intermediates for prepn. of 1,3-diazin-b 6-ones and uracils - Google Patents

Processes and intermediates for prepn. of 1,3-diazin-b 6-ones and uracils Download PDF

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CN1344259A
CN1344259A CN00805231A CN00805231A CN1344259A CN 1344259 A CN1344259 A CN 1344259A CN 00805231 A CN00805231 A CN 00805231A CN 00805231 A CN00805231 A CN 00805231A CN 1344259 A CN1344259 A CN 1344259A
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alkyl
hydrogen
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halogen
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V·卡梅斯瓦兰
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BASF SE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

An improved process and intermediate compounds (N) for the preparation of 2-(N,N-disubstituted)amino-4-(perfluoroalkyl)-1,3-oxazin-6-one compounds having structural formula (I) and an improved process for the preparation of 6-(perfluoroalkyl)uracil compounds having structural formula (V).

Description

Be used to prepare 1, the method and the intermediate of 3-oxazine-6-ketone and uridylic
Background of invention
6-(perfluoroalkyl) uracil compound can be used as weedkiller, and its preparation method is known in the art.6-(perfluoroalkyl) uracil compound can be by using 2-(N, N-two replaces) amino-4-(perfluoroalkyl)-1, and 3-oxazine-6-ketone and amine compound react and make.
Bull.Soc.Chem.Belg., 101 (4), 313-321 page or leaf (1992) discloses by using 3-amino-4,4,4-trifluoroacetic ethyl crotonate and imine acyl chloride hydrochloride (phosgeneiminium chloride) compound reacts and prepares 2-(N, the N-dialkyl group) amino-4-(trifluoromethyl)-1,3-oxazine-6-ketone compound.Yet, for preparation 2-(N, N-two replaces) amino-4-(perfluoroalkyl)-1,3-oxazine-6-ketone compound, this method is very not satisfactory, and this is because required imine acyl chloride hydrochloride compound is difficult to operation and quite expensive.Therefore, in this area, need to avoid using the imine acyl chloride hydrochloride compound to prepare 2-(N, N-two replaces) amino-4-(perfluoroalkyl)-1, the improving one's methods of 3-oxazine-6-ketone compound.
Therefore, the purpose of this invention is to provide preparation 2-(N, N-two replace) amino-4-(perfluoroalkyl)-1, the improving one's methods of 3-oxazine-6-ketone compound.
Another object of the present invention provides and can be used for preparing 2-(N, N-two replaces) amino-4-(perfluoroalkyl)-1, the midbody compound of 3-oxazine-6-ketone compound.
A further object of the invention provides improving one's methods of preparation 6-(perfluoroalkyl) uracil compound.
To those skilled in the art, by reading following specification sheets and claims, other purpose of the present invention and advantage will be conspicuous.
Summary of the invention
The invention provides 2-shown in the preparation formula I (N, N-two replaces) amino-4-(perfluoroalkyl)-1, the novel method of 3-oxazine-6-ketone compound
Figure A0080523100201
Wherein Z and Z 1Be C independently respectively 1-C 8Alkyl, perhaps Z and Z 1Form 4-7 unit ring, wherein ZZ with the atom that they connected 1By-(CH 2) 2O (CH 2) 2-or-(CH 2) m-representative, wherein m is an integer 3,4,5 or 6; And n is integer 1,2,3,4,5 or 6, comprising: (a) make beta-amino-β shown in the formula II-(perfluoroalkyl) acrylic compound
Figure A0080523100202
Wherein n as mentioned above, and Z 2Be C 1-C 6Alkyl or benzyl, wherein said benzyl can be chosen wantonly on phenyl ring by 1-3 halogen, C 1-C 4Alkyl or C 1-C 4Haloalkyl replaces, and reacts with carbamyl chlorine compound shown in alkali and the formula III
Figure A0080523100203
Wherein Z and Z 1As mentioned above, to form carbamide compound shown in the formula IV (b) make the reaction of formula IV urea and phosphorus pentahalides or oxalyl halogen.
The present invention also provides 6-shown in the preparation formula V (perfluoroalkyl) method of uracil compound
Figure A0080523100212
Wherein n is an integer 1,2,3,4,5 or 6; Z 3Be hydrogen or C 1-C 6Alkyl; With Q be C 1-C 6Alkyl or optional phenyl, benzyl, heteroaryl or the methylene radical heteroaryl that replaces, this method comprises that (a) makes carbamide compound shown in the formula IV
Figure A0080523100213
Wherein Z and Z 1Be C independently respectively 1-C 8Alkyl, perhaps Z and Z 1Form 4-7 unit ring, wherein ZZ with the atom that they connected 1By-(CH 2) 2O (CH 2) 2-or-(CH 2) m-representative, wherein m is an integer 3,4,5 or 6; Z 2Be C 1-C 6Alkyl or benzyl, wherein said benzyl can be chosen wantonly on phenyl ring by 1-3 halogen, C 1-C 4Alkyl or C 1-C 4Haloalkyl replaces; And n as mentioned above, with phosphorus pentahalides or oxalyl chloride reaction, to form 2-shown in the formula I (N, N-two replaces) amino-4-(perfluoroalkyl)-1,3-oxazine-6-ketone
Figure A0080523100221
(b) with 2-(N, N-two replaces) amino-4-(perfluoroalkyl)-1, amine compound reacts in the presence of acid or alkali shown in 3-oxazine-6-ketone and the formula VI
QNH 2
(VI) wherein Q as mentioned above to form 6-shown in the formula V (perfluoroalkyl) uracil compound, wherein Z 3Be hydrogen; (c) optional wherein Z 3It is the formula V alkylation of hydrogen.
The invention still further relates to carbamide compound new shown in the formula IV
Figure A0080523100222
Wherein Z and Z 1Be C independently respectively 1-C 8Alkyl, perhaps Z and Z 1Form 4-7 unit ring, wherein ZZ with the atom that they connected 1By-(CH 2) 2O (CH 2) 2-or-(CH 2) m-representative, wherein m is an integer 3,4,5 or 6; N is an integer 1,2,3,4,5 or 6; And Z 2Be C 1-C 6Alkyl or benzyl, wherein said benzyl can be chosen wantonly on phenyl ring by 1-3 halogen, C 1-C 4Alkyl or C 1-C 4Haloalkyl replaces.
Detailed Description Of The Invention
In the preferred embodiment of the invention, formula I 2-(N, N-two replaces) amino-4-(perfluoroalkyl)-1,3-oxazine-6-ketone compound makes like this: in the presence of first kind of solvent, with formula II beta-amino-β-(perfluoroalkyl) acrylic compound and alkali and the reaction of formula III carbamyl chlorine compound, preferably at-20 ℃-80 ℃ approximately, more preferably under about 0 ℃ of-50 ℃ of temperature, react, with production IV carbamide compound, choose wantonly then in the presence of second kind of solvent, with formula IV carbamide compound and phosphorus pentahalides or the reaction of oxalyl halogen, preferably at about 0 ℃-100 ℃, more preferably under about 20 ℃ of-50 ℃ of temperature, react.
The present invention also provides preparation preparation formula I2-(N, N-two replaces) amino-4-(perfluoroalkyl)-1, the method of 3-oxazine-6-ketone compound, comprise and choosing wantonly in the presence of second kind of solvent, with formula IV carbamide compound and phosphorus pentahalides or the reaction of oxalyl halogen, preferably about 0 ℃-100 ℃, more preferably under about 20 ℃ of-50 ℃ of temperature, react.
Advantageously, the invention provides and avoid using the imine acyl chloride hydrochloride compound to prepare 2-(N, N-two replace) amino-4-(perfluoroalkyl)-1, the improving one's methods of 3-oxazine-6-ketone compound.
The invention still further relates to carbamide compound shown in the formula IV that is used for the inventive method
Figure A0080523100231
Wherein Z and Z 1Be C independently respectively 1-C 8Alkyl, perhaps Z and Z 1Form 4-7 unit ring, wherein ZZ with the atom that they connected 1By-(CH 2) 2O (CH 2) 2-or-(CH 2) m-representative, wherein m is an integer 3,4,5 or 6; N is an integer 1,2,3,4,5 or 6; And Z 2Be C 1-C 6Alkyl or benzyl, wherein said benzyl can be chosen wantonly on phenyl ring by 1-3 halogen, C 1-C 4Alkyl or C 1-C 4Haloalkyl replaces.
Preferred formula IV compound is the formula IV compound that is defined as follows: wherein Z and Z 1Be C independently respectively 1-C 6Alkyl; Z 2Be C 1-C 4Alkyl; And n is 1.
Preferred formula IV carbamide compound of the present invention is the formula IV compound that is defined as follows: wherein Z and Z 1Identical, and represent methylidene or ethyl; Z 2Be methyl or ethyl; And n is 1.
The representative formula IV compound that is particularly useful in the inventive method comprises 3-[(N, the N-formyl-dimethylamino) amino]-4,4, the 4-trifluoroacetic ethyl crotonate, (Z)-; 3-[(N, the N-formyl-dimethylamino) amino]-4,4,4-trifluoro methyl crotonate, (Z)-; 3-[(N, N-diethylamino formyl radical) amino]-4,4, the 4-trifluoroacetic ethyl crotonate, (Z)-; 3-[(N, N-diethylamino formyl radical) amino]-4,4,4-trifluoro methyl crotonate, (Z)-; 3-[(N-tetramethyleneimine carbonyl) amino]-4,4, the 4-trifluoroacetic ethyl crotonate, (Z)-; With 3-[(N-tetramethyleneimine carbonyl) amino]-4,4,4-trifluoro methyl crotonate, (Z)-etc.
In another preferred embodiment of the present invention, the two keys in formula II and the IV compound mainly are (Z)-configuration.
Product formula I compound can separate like this: water dilutes reaction mixture, and with suitable extraction solvent extraction product.In lock out operation, can use extraction solvent commonly used, for example ether, ethyl acetate, toluene, methylene dichloride etc.
The alkali that is applicable to preparation formula IV carbamide compound includes but not limited to alkalimetal hydride, for example sodium hydride etc.; Basic metal C 1-C 6Alkoxide, for example potassium tert.-butoxide, sodium tert-butoxide etc.; Alkali metal hydroxide, for example potassium hydroxide, sodium hydroxide etc.; Alkaline carbonate, for example yellow soda ash, salt of wormwood etc.; Alkaline earth metal hydroxides, for example calcium hydroxide etc.; Alkaline earth metal carbonate, for example lime carbonate etc.; With lithium alkali, for example lithium alkylide comprises n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, lithium methide etc., and the dialkyl amido lithium comprises diisopropylaminoethyl lithium etc. and ring lithium amide, comprises tetramethyl piperidine lithium etc.Preferred first kind of alkali comprises alkalimetal hydride and basic metal C 1-C 6Alkoxide.
Be applicable to that the phosphorus pentahalides in the inventive method comprises phosphorus pentachloride, phosphorus pentabromide and pentaiodo phosphorus, phosphorus pentachloride is preferred.Be applicable to that oxalyl halogen of the present invention comprises oxalyl chloride, oxalyl bromine and oxalyl iodine, oxalyl chloride is preferred.
Can be used for first kind of solvent of the present invention and include but not limited to carboxylic acid amide, N for example, dinethylformamide, N,N-dimethylacetamide etc.; Ether, for example ether, tetrahydrofuran (THF), dioxane, 1,2-glycol dimethyl ether etc.; Nitrile, for example acetonitrile, propionitrile etc.; Dialkyl sulphoxide, for example methyl-sulphoxide etc.; With their mixture.Preferred first kind of solvent is N, dinethylformamide.
Be applicable to that second kind of solvent of the present invention includes but not limited to three oxyhalogen phosphorus, for example phosphoryl chloride etc.; Aromatic hydrocarbons, for example toluene, benzene, dimethylbenzene, mesitylene etc.; Halogenated aryl hydrocarbon, for example chlorobenzene, fluorobenzene etc.; Carboxylic acid amide, N for example, dinethylformamide, N,N-dimethylacetamide etc.; Aliphatic hydrocrbon, for example pentane, hexane, heptane etc.; Halogenated aliphatic hydrocarbon, for example methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; With their mixture.Preferred second kind of solvent is phosphorus oxychloride.
The preferred formula I compound that can make by the inventive method is that wherein Z and Z1 are C respectively independently 1-C 6Alkyl; And n is those formulas I compound of 1.
The inventive method is preferred for also preparing that wherein Z is identical with Z1, and represent methylidene or ethyl; And n is 1 formula I compound.
Formula I2-(N, N-two replaces) amino-4-(perfluoroalkyl)-1,3-oxazine-6-ketone compound can be used for preparation formula V weedicide 6-(perfluoroalkyl) uracil compound
Figure A0080523100261
Wherein n is an integer 1,2,3,4,5 or 6; Z 3Be hydrogen or C 1-C 6Alkyl; And Q is C 1-C 6Alkyl or optional phenyl, benzyl, heteroaryl or the methylene radical heteroaryl that replaces.
Formula V6-(perfluoroalkyl) uracil compound can advantageously make by comprising following method: (a) make carbamide compound shown in the formula IV
Figure A0080523100262
Wherein Z and Z 1Be C independently respectively 1-C 8Alkyl, perhaps Z and Z 1Form 4-7 unit ring, wherein ZZ with the atom that they connected 1By-(CH 2) 2O (CH 2) 2-or-(CH 2) m-representative, wherein m is an integer 3,4,5 or 6; Z 2Be C 1-C 6Alkyl or benzyl, wherein said benzyl can be chosen wantonly on phenyl ring by 1-3 halogen, C 1-C 4Alkyl or C 1-C 4Haloalkyl replaces; With n as mentioned above, with the reaction of phosphorus pentahalides or oxalyl halogen, to form 2-shown in the formula I (N, N-two replaces) amino-4-(perfluoroalkyl)-1,3-oxazine-6-ketone (b) with 2-(N, N-two replaces) amino-4-(perfluoroalkyl)-1, amine compound reacts in the presence of acid or alkali shown in 3-oxazine-6-ketone and the formula VI
QNH 2
(VI) wherein Q as mentioned above to form formula V 6-(perfluoroalkyl) uracil compound, wherein Z 3Be hydrogen; (c) optional wherein Z 3It is the formula V alkylation of hydrogen.
The acid that is applicable to preparation formula V compound comprises organic acid, includes but not limited to C 1-C 6Paraffinic acid, for example formic acid, acetate, propionic acid etc.; And mineral acid, include but not limited to hydrochloric acid, sulfuric acid, phosphoric acid etc.Preferred acid is acetate.
The alkali that is applicable to preparation formula V compound includes but not limited to three (C 1-C 6Alkyl) amine, for example Trimethylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine etc.; The heterocycle tertiary amine, for example 1,8-diazabicylo [5.4.0] 11-7-alkene (DBU), 1,5-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN), 1, the quinoline of the pyridine of 4-diazabicylo [2.2.2] octane, pyridine, replacement, quinoline, replacement etc.; With basic metal C 1-C 6Alkoxide, for example potassium tert.-butoxide, sodium tert-butoxide etc.Preferred second kind of alkali comprises 1,8-diazabicylo [5.4.0] 11-7-alkene and 1,5-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-5-alkene.
In preferred embodiment of the present invention, in the presence of the third solvent,, 3-oxazine-6-ketone and amine and acid-respons, preferably under about 20 ℃ of-150 ℃ of temperature, react 2-(N, N-two replacements) amino-4-(perfluoroalkyl)-1.The third solvent that is applicable to this reaction includes but not limited to carboxylic acid amide, N for example, dinethylformamide, N,N-dimethylacetamide etc.; Dialkyl sulphoxide, for example methyl-sulphoxide etc.; Aromatic hydrocarbons, for example toluene, benzene, dimethylbenzene, mesitylene etc.; Halogenated aryl hydrocarbon, for example chlorobenzene, fluorobenzene etc.; Aliphatic hydrocrbon, for example pentane, hexane, heptane etc.; Halogenated aliphatic hydrocarbon, for example methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Paraffinic acid, for example formic acid, acetate, propionic acid etc.; Ketone, for example acetone, methyl ethyl ketone etc.; Ether, for example ether, tetrahydrofuran (THF), dioxane, 1,2-glycol dimethyl ether etc.; Nitrile, for example acetonitrile, propionitrile etc.; Water; With their mixture.
Be applicable to that alkylation of the present invention comprises ordinary method known in the art.In preferred embodiment of the present invention, alkylation comprises, incites somebody to action wherein Z 3Be that the formula V compound of hydrogen and formula VII alkylogen or formula VIII sulfuric acid dialkyl react in the presence of alkali
XZ 3Or
Figure A0080523100281
(VII) wherein X is chlorine, bromine or iodine, and Z 3Be C 1-C 6Alkyl.
The alkali that is applicable to alkylation of the present invention comprises that those conventional alkali known in the art include but not limited to alkalimetal hydride, for example sodium hydride etc.; Basic metal C 1-C 6Alkoxide, for example potassium tert.-butoxide, sodium tert-butoxide etc.; Alkali metal hydroxide, for example potassium hydroxide, sodium hydroxide etc.; Alkaline carbonate, for example yellow soda ash, salt of wormwood etc.; Alkaline earth metal hydroxides, for example calcium hydroxide etc.; Alkaline earth metal carbonate, for example lime carbonate etc.
The preferred formula V compound that can prepare by the inventive method is formula V compound, its optical isomer, diastereomer and/or the dynamic isomer that is defined as follows: wherein n is 1; Z3Hydrogen or C1-C 4Sequence Table (A) General information: (Ⅱ) Title of Invention: Human DNA-PK-interacting protein 75 (Ⅲ) Serial Number: 7 (2) SEQ ID NO: 1 of the message: (Ⅰ) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2587bp (B) TYPE: nucleic acid (C) chain resistance: double-stranded (D) TOPOLOGY: linear (Ⅱ) MOLECULE TYPE: cDNA (Ⅹ ⅰ) SEQUENCE DESCRIPTION: SEQ ID NO: 1: 1 GTTAATGGCCACTGTACACCAGACTCAGCCTACAGTACAGGTGTTATTATCTACTTCTGA 61 ATTTGTTGGA GCATTGGACTTAATAGCAACAACACAAGAGGTTCTACAGCAGGAACTTCA 121 GGGCATTCAC AGTTTCCGGCATTTGGGATCACAGCTTTGTGAATTAGAAAAACTGATAGA 181 TAAAATGATG ATTGCAGAATTTTCTACTTATTCTCACAGTGACTTAAATAGACCACTGGA 241 AGATGACTGT CAAGTTTTAGAAGAGGAAAGACTAATATCTCTTGTATTTGGACTTTTAAA 301 ACAAAGAAAG CTTAATTTTTTAGAAATCTATGGTGAAAAAATGGTTATTACAGCAAAGAA 361 TATCATTAAA CAGTGTGTGATTAATAAAGTTTCACAAACAGAAGAAATAGACACAGATGT 421 TGTTGTGAAG CTTGCAGATCAGATGAGAATGTTGAATTTTCCCCAGTGGTTTGATCTGCT 481 CAAGGATATT TTCTCTAAGTTTACAATTTTCCTACAGAGAGTGAAGGCAACATTAAATAT 541 CATTCACAGT GTTGTTCTCTCAGTTCTTGACAAAAACCAAAGGACTAGAGAATTGGAAGA 601 GATTTCACAA CAGAAGAATGCTGCAAAAGATAATTCACTGGACACAGAGGTGGCTTATTT 661 AATCCATGAA GGCATGTTTATAAGTGATGCATTCGGTGAGGGTGAGCTAACACCTATAGC 721 AGTTGACACT ACCTCTCAAAGAAATGCATCTCCAAATAGTGAGCCCTGCAGCAGTGATTC 781 TGTATCCGAG CCAGAATGTACTACTGATTCTTCATCCAGCAAAGAGCACACATCATCATC 841 TGCTATTCCA GGAGGTGTGGATATTATGGTCAGTGAAGATATGAAATTAACTGACTCAGA 901 GCTAGGAAAG CTGGCAAATAATATCCAGGAATTATTATATAGTGCCTCAGATATATGCCA 961 TGATCGAGCT GTCAAATTTCTCATGTCAAGAGCAAAGGATGGTTTTCTTGAGAAGCTAAA 1021 TTCCATGGAATTCATAACACTTTCTAGATTAATGGAAACATTCATTTTAGACACCGAACA 1081 GATCTGTGGAAGAAAAAGCACGTCATTACTTGGAGCACTTCAGAGCCAAGCTATTAAGTT 1141 TGTAAATAGGTTTCATGAAGAGAGAAAAACCAAGCTCAGCCTCCTCTTAGACAATGAGCG 1201 CTGGAAGCAAGCAGATGTTCCTGCAGAATTTCAGGATCTTGTTGATTCTCTGTCAGATGG 1261 GAAGATTGCTTTACCTGAAAAAAAATCAGGAGCCACAGAAGAAAGGAAACCAGCTGAAGT 1321 TCTTATTGTCGAGGGACAACAGTATGCAGTTGTTGGAACCGTATTGCTGTTAATAAGAAT 1381 TATCCTTGAATATTGCCAGTGTGTGGATAACATCCCATCTGTTACTACTGACATGCTTAC 1441 TCGTCTGTCAGATTTATTGAAGTACTTCAATTCAAGAAGTTGCCAGTTAGTTCTTGGAGC 1501 TGGTGCACTGCAAGTTGTTGGACTAAAAACGATAACTACAAAAAATTTGGCTCTTTCTTC 1561 ACGATGTTTGCAGTTAATTGTGCACTACATTCCTGTGATCCGGGCTCATTTTGAAGCTCG 1621 ACTACCACCTAAGCAATATAGCATGCTTAGGCATTTTGATCATATCACTAAGGACTACCA 1681 TGATCACATAGCTGAAATATCAGCTAAGCTTGTAGCGATAATGGATAGCTTATTTGACAA 1741 GCTGTTATCTAAGTATGAAGTGAAGGCTCCTGTTCCTTCTGCCTGTTTCAGGAATATTTG 1801 TAAGCAAATGACAAAAATGCACGAAGCTATATTTGATCTCCTTCCAGAAGAACAAACACA 1861 GATGTTATTTTTAAGAATTAATGCAAGTTATAAACTCCACTTGAAAAAGCAGTTATCTCA 1921 CTTAAATGTGATAAATGATGGAGGACCTCAAAATGGGTTGGTCACAGCAGATGTAGCTTT 1981 TTACACTGGAAATCTTCAAGCCTTAAAAGGCCTTAAAGATTTGGACCTAAATATGGCCGA 2041 AATTTGGGAGCAGAAGAGGTGATGTCATCCTGGAAAACTGGGTAGTTCATCTGACCATGG 2101 GATGTGTTTGTTATGAAGAAAATCTGGATGCCTGTGATTCGAGAATTGAACCTGAAACCC 2161 AAAGTGAACTGGGGTGGGGGAAGGGAAAAAGGAAAGTATCAAGTGTTGGGAAACTGGATT 2221 CAGTGGGATCTACAAGGAATGTCATTTTTGTGCATCCTACAGTGAGGAGTAACTGATCAG 2281 GTGTCTATAACATTTTTCATTCTCTCTGGAAACAGACTCAGGTTTCTTTGGACCAAATCC 2341 AAAAGAACACATAGCTGTAACACAGCTGTAGTTGACTAGAATGCTCTGTATACTTTATAT 2401 TAAAAAATGCTTTGCATTTCTTCCAGTGCAATGAAATTCATATGGTGTCCCACCTTATTT 2461 AATGATGGTACAATTTAAAATCTTAGTCAACTTCTGTAGAAAGTTTTCTCTATGAAAGTA 2521 AAGCTGTTTGAAAAATTATTATTTTTTTACAGATCTTTCTATAAAAAATAAACATCTTTT 2581 GATTGCT (3) SEQ ID NO: 2 of the message: (Ⅰ) SEQUENCE CHARACTERISTICS: (A) LENGTH: 685 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (Ⅱ) MOLECULE TYPE: peptide (Ⅹ ⅰ) SEQUENCE DESCRIPTION: SEQ ID NO: 2: 1 Met Ala Thr Val His Gln Thr Gln Pro Thr Val Gln Val Leu Leu 16 Ser Thr Ser Glu Phe Val Gly Ala Leu Asp Leu Ile Ala Thr Thr 31 Gln Glu Val Leu Gln Gln Glu Leu Gln Gly Ile His Ser Phe Arg 46 His Leu Gly Ser Gln Leu Cys Glu Leu Glu Lys Leu Ile Asp Lys 61 Met Met Ile Ala Glu Phe Ser Thr Tyr Ser His Ser Asp Leu Asn 76 Arg Pro Leu Glu Asp Asp Cys Gln Val Leu Glu Glu Glu Arg Leu 91 Ile Ser Leu Val Phe Gly Leu Leu Lys Gln Arg Lys Leu Asn Phe 106 Leu Glu Ile Tyr Gly Glu Lys Met Val Ile Thr Ala Lys Asn Ile 121 Ile Lys Gln Cys Val Ile Asn Lys Val Ser Gln Thr Glu Glu Ile 136 Asp Thr Asp Val Val Val Lys Leu Ala Asp Gln Met Arg Met Leu 151 Asn Phe Pro Gln Trp Phe Asp Leu Leu Lys Asp Ile Phe Ser Lys 166 Phe Thr Ile Phe Leu Gln Arg Val Lys Ala Thr Leu Asn Ile Ile 181 His Ser Val Val Leu Ser Val Leu Asp Lys Asn Gln Arg Thr Arg 196 Glu Leu Glu Glu Ile Ser Gln Gln Lys Asn Ala Ala Lys Asp Asn 211 Ser Leu Asp Thr Glu Val Ala Tyr Leu Ile His Glu Gly Met Phe 226 Ile Ser Asp Ala Phe Gly Glu Gly Glu Leu Thr Pro Ile Ala Val 241 Asp Thr Thr Ser Gln Arg Asn Ala Ser Pro Asn Ser Glu Pro Cys 256 Ser Ser Asp Ser Val Ser Glu Pro Glu Cys Thr Thr Asp Ser Ser 271 Ser Ser Lys Glu His Thr Ser Ser Ser Ala Ile Pro Gly Gly Val 286 Asp Ile Met Val Ser Glu Asp Met Lys Leu Thr Asp Ser Glu Leu 301 Gly Lys Leu Ala Asn Asn Ile Gln Glu Leu Leu Tyr Ser Ala Ser 316 Asp Ile Cys His Asp Arg Ala Val Lys Phe Leu Met Ser Arg Ala 331 Lys Asp Gly Phe Leu Glu Lys Leu Asn Ser Met Glu Phe Ile Thr 346 Leu Ser Arg Leu Met Glu Thr Phe Ile Leu Asp Thr Glu Gln Ile 361 Cys Gly Arg Lys Ser Thr Ser Leu Leu Gly Ala Leu Gln Ser Gln 376 Ala Ile Lys Phe Val Asn Arg Phe His Glu Glu Arg Lys Thr Lys 391 Leu Ser Leu Leu Leu Asp Asn Glu Arg Trp Lys Gln Ala Asp Val 406 Pro Ala Glu Phe Gln Asp Leu Val Asp Ser Leu Ser Asp Gly Lys 421 Ile Ala Leu Pro Glu Lys Lys Ser Gly Ala Thr Glu Glu Arg Lys 436 Pro Ala Glu Val Leu Ile Val Glu Gly Gln Gln Tyr Ala Val Val 451 Gly Thr Val Leu Leu Leu Ile Arg Ile Ile Leu Glu Tyr Cys Gln 466 Cys Val Asp Asn Ile Pro Ser Val Thr Thr Asp Met Leu Thr Arg 481 Leu Ser Asp Leu Leu Lys Tyr Phe Asn Ser Arg Ser Cys Gln Leu 496 Val Leu Gly Ala Gly Ala Leu Gln Val Val Gly Leu Lys Thr Ile 511 Thr Thr Lys Asn Leu Ala Leu Ser Ser Arg Cys Leu Gln Leu Ile 526 Val His Tyr Ile Pro Val Ile Arg Ala His Phe Glu Ala Arg Leu 541 Pro Pro Lys Gln Tyr Ser Met Leu Arg His Phe Asp His Ile Thr 556 Lys Asp Tyr His Asp His Ile Ala Glu Ile Ser Ala Lys Leu Val 571 Ala Ile Met Asp Ser Leu Phe Asp Lys Leu Leu Ser Lys Tyr Glu 586 Val Lys Ala Pro Val Pro Ser Ala Cys Phe Arg Asn Ile Cys Lys 601 Gln Met Thr Lys Met His Glu Ala Ile Phe Asp Leu Leu Pro Glu 616 Glu Gln Thr Gln Met Leu Phe Leu Arg Ile Asn Ala Ser Tyr Lys 631 Leu His Leu Lys Lys Gln Leu Ser His Leu Asn Val Ile Asn Asp 646 Gly Gly Pro Gln Asn Gly Leu Val Thr Ala Asp Val Ala Phe Tyr 661 Thr Gly Asn Leu Gln Ala Leu Lys Gly Leu Lys Asp Leu Asp Leu 676 Asn Met Ala Glu Ile Trp Glu Gln Lys Arg (4) SEQ ID NO: 3 Information (Ⅰ) SEQUENCE CHARACTERISTICS (A) LENGTH: 25 bases (B) TYPE: nucleic acid (C) chain: single-chain (D) TOPOLOGY: linear (Ⅱ) MOLECULE TYPE: oligonucleotide (Ⅹ ⅰ) SEQUENCE DESCRIPTION: SEQ ID NO: 3: GTTAATGGCCACTGTACACCAGACT 25 (5) SEQ ID NO: 4 for information (Ⅰ) SEQUENCE CHARACTERISTICS (A) LENGTH: 24 bases (B) TYPE: nucleic acid (C) chain: single-chain (D) TOPOLOGY: linear (Ⅱ) MOLECULE TYPE: oligonucleotide (Ⅹ ⅰ) SEQUENCE DESCRIPTION: SEQ ID NO: 4: AGCAATCAAAAGATGTTTATTTTT 24 (6) SEQ ID NO: 5 Information (Ⅰ) SEQUENCE CHARACTERISTICS (A) LENGTH: 29 bases (B) TYPE: nucleic acid (C) chain: single-chain (D) TOPOLOGY: linear (Ⅱ) MOLECULE TYPE: oligonucleotide (Ⅹ ⅰ) SEQUENCE DESCRIPTION: SEQ ID NO: 5: CCCGGATCCATGGCCACTGTACACCAGAC 29 (7) SEQ ID NO: 6 Information (Ⅰ) SEQUENCE CHARACTERISTICS (A) LENGTH: 29 bases (B) TYPE: nucleic acid (C) chain: single-chain (D) TOPOLOGY: linear (Ⅱ) MOLECULE TYPE: oligonucleotide (Ⅹ ⅰ) SEQUENCE DESCRIPTION: SEQ ID NO: 6: CCCCTCGAGTCACCTCTTCTGCTCCCAAA 29 8) SEQ ID NO: 7 information about: (Ⅰ) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (Ⅱ) MOLECULE TYPE: peptide (Ⅹ ⅰ) SEQUENCE DESCRIPTION: SEQ ID NO: 7: NH2-Met-Ala-Thr-Val-His-Gln-Thr-Gln-Pro-Thr-Val-Gln-Val-Leu-Leu-OH ...
Figure A0080523100282
G is CH2Or chemical bond; G1CX5Or N; G2CX4Or N; X1Hydrogen, halogen or the optional C that is replaced by an epoxy radicals1-C 6Alkyl, X2Hydrogen, halogen, NRR1、CO 2R 2、C(O)R 3、OR 4、SO 2R 5、SO 2NR 6R 7、 C(R 8)(OR 9) 2、C(R 10)＝NOR 11、 C(R 12)＝C(R 13)-C(OR 14)＝NOR 15、CH 2O-NCO 2R 16, optional by a C1-C 6Alkoxyl or one or two C1-C 41 of alkyl replacement, 3-dioxolane, optional by a C1-C 6Alkoxyl or one or two C1-C 41 of alkyl replacement, 3-dioxolone, optional by a CO2R 2Group and the C that halogen atom replaces1-C 4Alkyl, and X3Hydrogen, halogen, C1-C 4Haloalkyl, CO2R 17, cyano group, C1-C 4Halogenated alkoxy, OR18Or C1-C 4Alkyl, perhaps work as X1And X2While with their connected atoms, connecting together, they can form 5 yuan or 6 rings, wherein X1X 2Or X2X 1By following representative :-OC (R20)(R 21)O-、-CH 2S(O) pN(R 22)-、-SC(R 23)＝N-、 -CH＝CH-CH(R 11)O-、-OC(O)N-、-SC(R 24)＝N-、-ON(R 25)C(O)-、 -OC(CO 2R 26)＝C(R 27)-、-NC(R 28)＝C(SR 29)-、-CH＝C(CO 2R 30)O-、 -CH 2CH(R 31) O-or-OC (R32)(R 33) C (O)-, perhaps work as X2And X3While with their connected atoms, connecting together, they can form 5 yuan or 6 rings, wherein X2X 3Or X3X 2By following representative :-NC (R34)＝NC(S)-、-N(R 35)N＝C(R 36)-、-N(R 37)C(R 38)＝N-、 -N(R 38)C(O)CH 2O-、-N(R 39)C(O)CH＝CH-、-S-N＝C(R 40)-、 -O-N＝C(R 41)-、-N＝N-N(R 42)-、-C(R 43)(R 44)C(O)N(R 45)-or-N (R46)C(O)C(R 47)(R 48)-； X 4Hydrogen, halogen or OR19； X 5It is hydrogen or halogen; R, R56、R 64、R 69、R 70、R 77And R91Be hydrogen, SO independently respectively2R 49、C 1-C 4Alkyl, C3-C 7Cycloalkyl, C3-C 6Alkenyl, C3-C 6Alkynyl group, phenyl or benzyl; R1Hydrogen, SO2R 50、C(O)R 51, amino or optional by CO2R 52Or C (O) R53The C that replaces1-C 4Alkyl; R2、R 16、R 17、R 26、R 30、R 68、R 75、R 76、R 82And R88Be hydrogen, C independently respectively1-C 8Haloalkyl, C3-C 8Alkenyl, C3-C 6Alkynyl group, phenyl, benzyl, furfuryl, pyridine radicals, thienyl or C1-C 4Alkyl, described group is optional by CO2R 54, morpholine or C (O) R55Replace, perhaps alkali metal, alkaline-earth metal, ammonium or organic ammonium cation; R3、R 66、R 67、R 81、R 85And R89Be hydrogen, C independently respectively1-C 6Alkyl, C3-C 6Alkenyl, C3-C 6Alkynyl group, NR56R 57, phenyl or benzyl; R4、R 18、R 19And R65Be hydrogen, C independently respectively1-C 6Alkyl, C3-C 6Alkenyl, C3-C 6Alkynyl group, C1-C 4Haloalkyl, C (O) R58、C(S)R 59Or benzyl; R5And R72Be C independently respectively1-C 6Alkyl, C1-C 6Haloalkyl, NR60R 61, imidazoles or indazole; R6、R 11、R 12、R 14、R 15、R 20、R 21、R 22、R 25、R 28、R 29、R 31、R 32、R 33、 R 35、R 45、R 46、R 63And R80Be hydrogen or C independently respectively1-C 4Alkyl; R7Hydrogen, C3-C 6Alkenyl, C3-C 6Alkynyl group, benzyl or C1-C 4Alkyl, described group can be chosen wantonly by cyano group or C (O) R62Replace; R8And R27Be hydrogen, C independently respectively1-C 4Alkyl or C1-C 4Alkoxyl; R9And R90Be C independently respectively1-C 6Alkyl; R10Hydrogen, C1-C 6Alkyl, phenyl or benzyl; R13、R 24And R36Be hydrogen, C independently respectively1-C 6Alkyl or halogen; R23Hydrogen or NR63R 64； R 34Hydrogen, C1-C 4Alkyl or C1-C 4Haloalkyl; R37Hydrogen, C1-C 4Alkyl or C2-C 8The alkoxyl alkyl; R38And R39Be hydrogen, C independently respectively1-C 4Alkyl, C1-C 4Haloalkyl, C3-C 6Alkenyl or C3-C 6Alkynyl group; R40、R 41And R42Be hydrogen, halogen, cyano group, OR independently respectively65、C(O)R 66、C(S)R 67、 CO 2R 68、C(＝NOR 69)、C 1-C 8Alkyl, C3-C 7Cycloalkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group, wherein each group can be chosen arbitrarily combined following group wantonly and replaces: 1-6 halogen atom, a 1-3 C1-C 10Alkoxyl, 1 or 2 C1-C 6Halogenated alkoxy, 1 or 2 NR70R 71, 1 or 2 S (O)qR 72, 1 or 2 cyano group, 1 or 2 C3-C 7Cycloalkyl, an OSO2R 73, 1 or 2 C (O) R74, 1 or 2 CO2R 75, 1 or 2 C (O) SR76, 1 or 2 C (O) NR77R 78, a 1-3 OR79, 1 or 2 P (O) (OR80) 2, one optional by 1-3 C1-C 4Alkyl replace 1, the 3-dioxolane or one optional by 1-3 C1-C 4Alkyl replace 1, the 3-dioxane, perhaps phenyl or benzyl, the optional arbitrarily combined following group of described phenyl or benzyl replaces: 1-3 halogen atom, a 1-3 C1-C 6Alkyl, a 1-3 C1-C 6Alkoxyl, a C3-C 7Cycloalkyl, a C1-C 4Haloalkyl, a C1-C 4Alkylthio group, cyano group, nitro, a C (O) R81, a CO2R 82, an OR83, a SR84, a C1-C 6Alkoxyl methyl, a methylol, a C3-C 8Alkenyloxy methyl or a C1-C 8The halogenated alkoxy methyl; R43、R 44、R 47And R48Be hydrogen, C independently respectively1-C 4Alkyl, C1-C 4Haloalkyl, C3-C 6Alkenyl, C3-C 6Alkynyl group or C3-C 7Cycloalkyl, perhaps R43And R44Or R47And R48Form C together with atom that they connect3-C 7Cycloalkyl; R49、R 50And R86Be C independently respectively1-C 6Alkyl, NR93R 94、C 1-C 4Haloalkyl, C3-C 6Alkenyl, C3-C 6Alkynyl group or benzyl; R51、R 52、R 53、R 54、R 55、R 57、R 58、R 59、R 60、R 61、R 62、R 71、R 73、R 74、 R 78、R 87And R92Be hydrogen, C independently respectively1-C 6Alkyl, C3-C 7Cycloalkyl, C1-C 6Haloalkyl, C3-C 6Alkenyl, C3-C 6Alkynyl group, phenyl or benzyl; R79、R 83And R84Be hydrogen, C (O) R independently respectively85、SO 2R 86、C 1-C 6Haloalkyl, C2-C 6Alkenyl, C5-C 8Cycloalkenyl group, C2-C 6Alkynyl group, phenyl, benzyl or C1-C 10Alkyl, described group is optional to be replaced by following group: hydroxyl, benzyloxy, OC (O) R87、C 1-C 6Alkoxyl, CO2R 88、C(O)R 89、C(OR 90) 2、C(O)NR 91R 92Or cyano group; R93And R94Be hydrogen, C independently respectively1-C 4Haloalkyl, C2-C 6Alkenyl, C3-C 8Cycloalkyl, C1-C 8Alkyl, described group is optional by 1 or 2 C1-C 4Alkoxyl or cyano group alkyl replace, perhaps benzyl or phenyl, and the optional arbitrarily combined following group of described phenyl or benzyl replaces: 1-3 halogen atom, a 1-3 C1-C 4Alkyl, a 1-3 C1-C 4Haloalkyl, a 1-3 C1-C 4Alkoxyl, a 1-3 C1-C 4Halogenated alkoxy, a cyano group or a nitro, and work as R93And R94When the atom that is connected with them connects together, the two ring heterocycles that they can form 5 yuan of-12 yuan of monocycles or condense, described ring can be chosen wantonly by one or more halogen, cyano group, nitro, amino, hydroxyl, C of being independently selected from1-C 4Alkyl, C1-C 4Haloalkyl, C1-C 4Alkoxyl, C1-C 4Halogenated alkoxy and C1-C 4The group of halogenated alkyl sulfonyl replaces; And p and q are respectively 0,1 or 2 independently.
The preferred formula V herbicide that can prepare by the inventive method is those compounds that are defined as follows: wherein n is 1; Z3Hydrogen or methyl; Q is
Figure A0080523100321
G is CH2Or chemical bond; G1CX5Or N; G2CX4Or N; X1Hydrogen, fluorine or the optional C that is replaced by an epoxy radicals1-C 3Alkyl, X2Hydrogen, halogen, NRR1、CO 2R 2、C(O)R 3、OR 4、SO 2R 5、SO 2NR 6R 7、 C(R 8)(OR 9) 2、C(R 10)＝NOR 11、 C(R 12)＝C(R 13)-C(OR 14)＝NOR 15、CH 2O-NCO 2R 16, optional by a C1-C 6Alkoxyl or one or two C1-C 41 of alkyl replacement, 3-dioxolane, optional by a C1-C 6Alkoxyl or one or two C1-C 41 of alkyl replacement, 3-dioxolone, optional by a CO2R 2Group and the C that halogen atom replaces1-C 4Alkyl, and X3Hydrogen, halogen, C1-C 4Haloalkyl, CO2R 17, cyano group, C1-C 4Halogenated alkoxy, OR18Or C1-C 4Alkyl, perhaps work as X1And X2While with their connected atoms, connecting together, they can form 5 yuan or 6 rings, wherein X1X 2Or X2X 1By following representative :-OC (R20)(R 21)O-、-CH 2S(O) pN(R 22)-、-SC(R 23)＝N-、 -CH＝CH-CH(R 11)O-、-OC(O)N-、-SC(R 24)＝N-、-ON(R 25)C(O)-、 -OC(CO 2R 26)＝CH-、-NC(R 28)＝C(SR 29)-、-CH＝C(CO 2R 30)O-、 -CH 2CH(R 31) O-or-OC (R32)(R 33) C (O)-, perhaps work as X2And X3While with their connected atoms, connecting together, they can form 5 yuan or 6 rings, wherein X2X 3Or X3X 2By following representative :-NC (R34)＝NC(S)-、-N(R 35)N＝C(R 36)-、-N(R 37)C(R 38)＝N-、 -N(R 38)C(O)CH 2O-、-N(R 39)C(O)CH＝CH-、-S-N＝C(R 40)-、 -O-N＝C(R 41)-、-N＝N-N(R 42)-、-C(R 43)(R 44)C(O)N(R 45)-or-N (R46)C(O)C(R 47)(R 48)-； X 4Hydrogen, halogen or OR19； X 5It is hydrogen or halogen; R, R64、R 69, and R77Be hydrogen, SO independently respectively2R 49Or C1-C 4Alkyl; R1Hydrogen, SO2R 50、C(O)R 51, amino or optional by CO2R 52Or C (O) R53The C that replaces1-C 4Alkyl; R2、R 16、R 17、R 26、R 30、R 58、R 75、R 76、R 82And R88Be hydrogen, C independently respectively3-C 6Alkenyl or C1-C 4Alkyl, described group is optional by CO2R 54, morpholine or C (O) R55Replace; R3、R 68、R 67、R 85And R89Be hydrogen, C independently respectively1-C 4Alkyl or NR56R 57； R 4、R 18And R19Be hydrogen, C independently respectively1-C 4Alkyl, C1-C 4Haloalkyl, C (O) R58、 C 3-C 4Alkenyl or C3-C 4Alkynyl group; R56SO2R 49； R 57Hydrogen or C1-C 4Alkyl; R5And R72Be NR independently respectively60R 61Or indazole; R6、R 11、R 12、R 14、R 15、R 20、R 21、R 22、R 25、R 28、R 29、R 31、R 32、R 33、 R 35、R 45、R 46And R80Be hydrogen or methyl independently respectively; R7Optional by cyano group or C (O) R62The C that replaces1-C 4Alkyl; R8Hydrogen or C1-C 4Alkoxyl; R9And R90Be C independently respectively1-C 4Alkyl; R10Hydrogen or C1-C 3Alkyl; R13、R 24And R36Be hydrogen or chlorine independently respectively; R23NR63R 64； R 34C1-C 3Haloalkyl; R37C2-C 4The alkoxyl alkyl; R38And R39Be C independently respectively1-C 3Haloalkyl, C1-C 3Alkyl or propargyl; R40、R 41And R42Be hydrogen, C (O) R independently respectively66、C(S)R 67、CO 2R 68、C(＝NOR 69), the C that replaces of optional arbitrarily combined following group1-C 3Alkyl: 1 or 2 halogen atom, 1 or 2 C1-C 3Alkoxyl, 1 or 2 C1-C 3Halogenated alkoxy, a SO2R 72, 1 or 2 cyano group, a C3-C 5Cycloalkyl, an OSO2R 73, C (O) R74, a CO2R 75, C (O) SR76, C (O) NR77R 78, a 1-2 OR79, P (O) (OR80) 2, one 1,3-dioxolane group or one 1,3-dioxane group, perhaps phenyl, the optional arbitrarily combined following group of described phenyl replaces: a halogen atom, 1 or 2 methyl, a methoxyl group, a halo methyl or an OR83； R 43、R 44、R 47And R48Be hydrogen or methyl, perhaps R independently respectively43And R44Or R47And R48Form cyclopropyl together with atom that they connect; R49、R 50And R86Be C independently respectively1-C 4Alkyl or NR93R 94； R 51、R 52、R 53、R 54、R 55、R 58、R 60、R 61、R 62、R 73、R 74、R 78And R87Be hydrogen, C independently respectively1-C 4Alkyl or C1-C 4Haloalkyl; R79And R83Be hydrogen, C (O) R independently respectively85、SO 2R 86、C 1-C 4Haloalkyl, C3-C 4Alkenyl or C1-C 3Alkyl, described group is optional to be replaced by following group: an OC (O) R87、 CO 2R 88、C(O)R 89、C(OR 90) 2Or cyano group; R93And R94Be hydrogen or C independently respectively1-C 8Alkyl; And p is 0,1 or 2.
The inventive method is particularly useful for 6-shown in the preparation formula IX (trifluoromethyl) uracil compound
Figure A0080523100351
Z wherein 3Be hydrogen or methyl; X 5It is hydrogen or halogen; R 40Be hydrogen, C (O) R 66, C (S) R 67, CO 2R 68, the C that replaces of optional arbitrarily combined following radicals 1-C 3Alkyl: 1 or 2 halogen atom, 1 or 2 C 1-C 3Alkoxyl group, 1 or 2 C 1-C 3Halogenated alkoxy, a SO 2R 72, 1 or 2 cyano group, a C 3-C 5Cycloalkyl, an OSO 2R 73, 1 or 2 OR 79, P (O) (OR 80) 2, one 1,3-dioxolane group or one 1,3-dioxane group, perhaps phenyl, the optional arbitrarily combined following radicals of described phenyl replaces: a halogen atom, 1 or 2 methyl, a methoxyl group, a halogenated methyl or an OR 83R 66, R 67, R 85And R 89Be hydrogen, C independently respectively 1-C 4Alkyl or NR 56R 57R 56Be SO 2R 49R 57Be hydrogen or C 1-C 4Alkyl; R 49And R 86Be C independently respectively 1-C 4Alkyl or MR 93R 94R 93And R 94Be hydrogen or C independently respectively 1-C 8Alkyl; R 68And R 88Be hydrogen, C independently respectively 3-C 6Alkenyl or C 1-C 4Alkyl, described group is optional by CO 2R 54, morpholine or C (O) R 55Replace; R 54, R 55, R 60, R 61, R 73And R 87Be hydrogen, C independently respectively 1-C 4Alkyl or C 1-C 4Haloalkyl; R 72Be NR 60R 61Or indazole; R 79And R 83Be hydrogen, C (O) R independently respectively 85, SO 2R 86, C 1-C 4Haloalkyl, C 3-C 4Alkenyl or C 1-C 3Alkyl, described group is optional to be replaced by following radicals: an OC (O) R 87, CO 2R 88, C (O) R 89, C (OR 90) 2, or cyano group; R 80Be hydrogen or methyl; And R 90Be C 1-C 4Alkyl.
The example of above-mentioned halogen has fluorine, chlorine, bromine and iodine.Term " halogenated methyl ", " C 1-C 4Haloalkyl ", " C 1-C 8Haloalkyl ", " C 1-C 3Halogenated alkoxy ", " C 1-C 4Halogenated alkoxy " and " C 1-C 8The haloalkoxy ylmethyl " be defined as and have the substituent methyl of one or more halogen atoms, C 1-C 4Alkyl, C 1-C 8Alkyl, C 1-C 3Alkoxyl group, C 1-C 4Alkoxyl group or C 1-C 8Alkoxy methyl.In above-mentioned formula V, basic metal comprises sodium, potassium and lithium, and alkaline-earth metal comprises calcium and magnesium.Be applicable to that organic ammonium positively charged ion of the present invention includes but not limited to by connecting the group that positively charged nitrogen-atoms that 1-4 aliphatic group and each aliphatic group contain 1-16 carbon atom constitutes.
In above-mentioned formula V, 5 yuan of-12 yuan of monocycles or condensed bicyclic heterocycles include but not limited to benzoglyoxaline, imidazoles, imidazoline-2-sulfur-one, indoles, isatoic anhydride (isatoicanhydride), morpholine, piperazine, piperidines, purine, pyrazoles, pyrroles, tetramethyleneimine and 1,2, the 4-triazole ring, wherein each heterocycle heterocycle can be chosen wantonly by one or more halogen, cyano group, nitro, amino, hydroxyl, C of being independently selected from 1-C 4Alkyl, C 1-C 4Haloalkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy and C 1-C 4The group of halogenated alkyl sulfonyl replaces.
Raw material formula II beta-amino-β-(perfluoroalkyl)-acrylic compound is known in the art, and can make according to the method for describing in following document: U.S.5,777,154; " heterocyclic chemistry magazine " Journal of Heterocyclic Chemistry, 9, the 513-522 pages or leaves (1972); With Institute of Chemistry, Urals ScientificCenter, Academy of Sciences of the USSR, Sverdlovsk, 1442-1447 page or leaf (1987)-English translation of ZhurnalOrganicheskoi Khimii, 22 (8), 1603-1609 page or leaf (1986).
Formula III carbamyl chlorine compound is known in the art, and can make by ordinary method.In addition, the commercially available acquisition of some formula III carbamyl chlorine compounds.
Amine compound shown in the formula VIa
Figure A0080523100371
X wherein 1, X 5And R 40As mentioned above, can be shown in synthetic schemes schema I as described below making: with the cyclization of formula X ketone, forming formula XI nitro benzisothiazole, and use the conventional reduction agent for example in acetate, formula XI compound to be reduced with sulphur and ammonium hydroxide or ammonia with iron.
Synthetic schemes schema I
Figure A0080523100372
The raw material of amine compound shown in the formula VIb X wherein 1, X 5And R 41As mentioned above, can be shown in synthetic schemes schema II as described below making: choose formula XII ketone and hydroxy amine hydrochloric acid salt wantonly in the presence of sodium acetate reaction, with production XIII oxime, with alkali for example potassium hydroxide with the cyclization of formula XIII compound, with production XIV nitro benzoisoxazole, and use the conventional reduction agent for example in acetate, formula XIV compound to be reduced with tin chloride (II).
Synthetic schemes schema II
Figure A0080523100391
Perhaps, formula XIV nitro benzoisoxazole can be shown in synthetic schemes schema III as described below making: formula XV ketone and hydroxy amine hydrochloric acid salt are chosen wantonly in for example reaction in the presence of the sodium acetate of alkali, with production XVI oxime, at alkali for example in the presence of the triethylamine, with 1,1 '-carbonyl dimidazoles is the cyclization of formula XVI compound, with production XVII benzoisoxazole, and with ordinary method for example nitric acid/sulfuric acid mixture is nitrated with formula XVII compound.
Synthetic schemes schema III
Figure A0080523100411
R wherein 40And R 41Be OR 65Formula XI and the XIV midbody compound can be shown in synthetic schemes schema IV as described below making: for example nitric acid/sulfuric acid mixture is nitrated with formula XVIII benzoisoxazole-3-alcohol or benzisothiazole-3-alcohol to use conventional nitrating agent, generate 5-nitro benzo isoxazol-3-ol or 5-nitro benzisothiazole-3-alcohol with formula XIX, and for example in the presence of the salt of wormwood formula XIX compound and formula XX electrophilic reagent are reacted at alkali.
Synthetic schemes schema IV
Figure A0080523100431
R wherein 40And R 41The formula XI and the XIV midbody compound that are Cl or Br can be shown in synthetic schemes schema V, by formula XIX 5-nitro benzo isoxazol-3-ol or 5-nitro benzisothiazole-3-alcohol are made with phosphorus oxychloride, tribromo oxygen phosphorus or phosphorus pentabromide reaction.
Synthetic schemes schema V
Figure A0080523100441
From following embodiment, can be expressly understood other method of preparation formula VIa and VIb amine compound.In addition, available ordinary method known in the art changes into other formula VIa, VIb, XI and XIV compound with some formula VIa, VIb, XI and XIV compound.
Other formula VI amine compound is known in the art, and can make according to the method for describing in following document:
EP561319-A; EP540023-A; EP545206-A; EP542685-A; EP473551-A; EP476697-A; EP489480-A; EP496595-A; EP420194-A; EP648749-A; EP705829-A; EP714602-A; JP9241245; JP9301973; 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; WO93/14073; WO94/10155; WO94/24128; WO91/07393; WO91/107392; WO95/04461; WO95/05079; WO95/05080; WO95/17096; WO95/25725; WO95/29168; WO95/32952; WO95/33746; WO96/02518; WO96/08151; WO96/14315; WO96/28442; WO96/34859; WO96/35679; WO97/01541; WO97/01542; WO97/05118; WO97/07105; WO97/08170; WO97/08171; WO97/08953; WO97/12884; WO97/12886; WO97/29094; WO97/29105; WO97/34484; WO97/35845; WO97/42176; WO97/42188; WO97/45418; WO97/47607; WO98/02422; WO98/06706; WO98/08824; WO98/27057; WO98/27067; WO98/27082; And WO98/27088, etc.
In order to help further to understand the present invention, more specifically describe the present invention in detail with following embodiment.Scope of the present invention is not subjected to the restriction of these embodiment, the whole theme that limits in its book of being included in.
Embodiment 1
Preparation 3-[(N, the N-formyl-dimethylamino) amino]-4,4, the 4-[trifluoroacetic ethyl crotonate, (Z)-
Figure A0080523100451
Under 5 ℃, nitrogen atmosphere, with 60 minutes with 3-amino-4,4, (18.4g, (60%/mineral oil, 9.6g is 250mmol) at N, in the stirred solution in the dinethylformamide (60mL) 100mmol) to be added to sodium hydride for the 4-trifluoroacetic ethyl crotonate.This reaction mixture is risen to room temperature, and kept 15 minutes in room temperature, be cooled to 5 ℃, (21.6g 200mmol) handles with dimethylcarbamyl chloride in 60 minutes.Then gained solution is risen to room temperature and kept 2 hours, water (150mL) dilution, and with ethyl acetate (2 * 150mL) extract.With the organic layer drying that merges, filter and concentrate, remove the mineral oil reservoir, obtained resistates.Use silica gel by flash column chromatography purifying resistates,, obtained this title product, be yellow liquid (18.1g, 71% yield) with 85: 15 hexane/ethyl acetate eluant solutions: 1H NMR (DMSO-d 6) δ 9.18 (s, 1H), 5.85 (s, 1H), 4.20 (q, 2H), 2.89 (s, 6H), 1.18 (t, 3H); 19F NMR δ-65.7 (s).
Use substantially the same method, made following compound:
Figure A0080523100461
(Z)-configuration Z Z 1Z 2Mp (℃) yield (%) C 2H 5C 2H 5C 2H 5Yellow oil 88
-(CH 2) 4-?????????C 2H 5???54-57????????37CH 3????????????CH 3????CH 3C 2H 5??????????C 2H 5??CH 3
-(CH 2) 4-?????????CH 3
Embodiment 2
Preparation 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazine-6-ketone
Figure A0080523100471
With phosphorus pentachloride (4.16g 0.02mol) divides 3 batch processing 3-[N-(N, N-formyl-dimethylamino) amino with 15 minutes interval]-4; 4,4-trifluoroacetic ethyl crotonate (5.08g, 0.02mol) solution in phosphorus oxychloride (3mL); stirred 30 minutes, with ice and water treatment.With ethyl acetate extraction gained aqueous mixture.Organic layer is used saturated sodium bicarbonate and water washing successively, and evaporation has obtained this title product, be white solid (3.9g, 93.8% yield), 1H and 19F NMR confirms that it is identical with the sample that makes by literature method (Bull.Soc.Chem.Belg.101,313,1992).Be further purified this title product (74.5% crystallization yield) by recrystallization from heptane.
Use substantially the same method; but with 3-[N-(N, N-diethylamino formyl radical) amino]-4,4; 4 trifluoro crotonates replace 3-[N-(N; the N-formyl-dimethylamino) amino]-4,4,4-trifluoro crotonate; made 2-diethylamino-4-(trifluoromethyl)-6H-1; 3-oxazine-6-ketone is oily matter (86% crude product yield, 65% purification yield).
Embodiment 3
Preparation 3-sec.-propyl-6-(trifluoromethyl)-2,4 (1H, 3H)-pyrimidine dione
Figure A0080523100481
(1.2g, 20.3mmol) with 1, (DBU 6mL) is added to 2-dimethylamino-4-trifluoromethyl-6H-1 to 8-diazabicylo [5.4.0] 11-7-alkene, and (4.0g is 19.2mmol) in the solution in dimethylbenzene (34mL) for 3-oxazine-6-ketone with isopropylamine.100 ℃ of heating 3 hours, cooling with 5wt.%HCl (40mL) washing, and was used ethyl acetate extraction with the gained reaction mixture.The organic phase that merges is concentrated, and develop with heptane.Filter out solid and dry, obtained this title product, be yellow powder (2.3g, 54% yield, mp127-129 ℃), its 1H NMR (DMSO-d 6) δ 6.11 (1H, s), 4.96 (1H, sp), 1.35 (6H, d); With 19F NMR δ-68.9 (s) has confirmed that it is the purpose product.
Use substantially the same method, but be to use suitable amine, obtained following compound:
Q acid/alkali solvent mp (℃) yield (%) (S)-(+)-CH (CH 3) C 2H 5DBU toluene 92-95 27 (R)-(-)-CH (CH 3) C 2H 5DBU dimethylbenzene 94-97 19 CH 3CO 2H CH 3CO 2H white powder 47
Figure A0080523100493
CH 3CO 2H toluene 169-172 74
Figure A0080523100494
CH 3CO 2H toluene 219-222 78
Embodiment 4
Preparation 2 '-chloro-2-methoxyl group-5-methyl-5 '-nitro benzophenone
With aluminum chloride (33.3g, 25.0mmol) mixture in methylene dichloride is cooled to about 5 ℃, last 1 hour with p-methyl anisole (31.6g, 25.0mmol) handle, simultaneously with the temperature maintenance of reaction mixture below 10 ℃, last 20 minutes with 2-chloro-5-nitrobenzoyl chloride (50.0g, 22.7mmol) solution-treated in methylene dichloride, temperature with reaction mixture remains on below 10 ℃ simultaneously, rises to room temperature and stirring at room 60 minutes, pours on ice.The gained aqueous mixture is handled with concentrated hydrochloric acid (50mL), and used dichloromethane extraction.With the organic extract dried over mgso, and vacuum concentration, yellow solid obtained.Solid is placed in Tim Koogle's distiller in 40 ℃ removes remaining p-methyl anisoles, obtained this title product,, identify by the NMR spectroscopic analysis for light brown solid (68.8g, 99.1%).
Use substantially the same method, made following compound:
Figure A0080523100511
W W 1W 2W 3W 4Mp ℃ of H I H H OCH 3115-116.5H H CH 3H OCH 3H H C 2H 5H HH CH 3CH 3H OCH 3H H OCH 3H H 108-112H C 2H 5H H OCH 398-99.5H H OCH 3H CH 391-92H H CH 3H H 95.5-96.5H H SCH 3H H 127-128H H CH 3H OCH 391-92.5H H C 2H 5H HH H Cl H H 88.5-90.5H H F H H 68-69.5H Cl H H OCH 3124-126H OCH 3H H OCH 371-73H H OCH 3H OCH 398-100H CH 3CH 3H OCH 3127-129H H Cl H OCH 396-99CH 3H CH 3H OCH 3108.5-110H H H CH 3OCH 371-74H H N (CH 3) SO 2CH 3H HH CH 3Cl H OCH 3126-128W W 1W 2W 3W 4Mp ℃ of H CH 3H CH 3OCH 3110-112CH 3CH 3CH 3H OCH 3104-106H CH (CH 3) 2H H OCH 369-71H CH 3H H HH H H H CNH H H H OCH 3H OCH 3H H HH F H H OCH 3H H F H OCH 3H H H H SCH 3H H H H CH 3H H H H FH SCH 3H H HH H OCH 3H HH-(CH 2) 3-H OCH 3
Embodiment 5
Preparation 3-(tolyl between the 6-methoxyl group)-5-nitro-1, the 2-benzisothiazole
Figure A0080523100521
With ammonium hydroxide (350mL 30% solution, 270mmol) be added to 2 '-chloro-2-methoxyl group-5-methyl-5 '-nitro benzophenone (68.7g, 22.5mmol) and sulphur (7.57g is 23.6mmol) at N, in the mixture in the dinethylformamide.The gained reaction mixture was stirred 19.5 hours at 80 ℃, be cooled to 40 ℃, use ammonium hydroxide (50mL 30% solution) to handle again, stirred 25 hours at 80 ℃, cooling, and pour in the ice.The gained aqueous mixture is filtered, obtained this title product,, identify by the NMR spectroscopic analysis for yellow solid (63.5g, 93.90).
Use substantially the same method, made following compound:
Figure A0080523100531
W W 1W 2W 3W 4Mp ℃ of H H CH 3H OCH 3201-203H CH 3CH 3H OCH 3199-200H CH 3H H H 116.5-117.5H H Cl H OCH 3229-231H H H CH 3OCH 3134-136H H H H CN 187.5-189H H H H OCH 3193-198H H OCH 3H H 201-203H OCH 3H H H 174-175H F H H OCH 3224-226H C 2H 5H H OCH 3153-154.5H H CH 3H H 188-189H H N (CH 3) SO 2CH 3H HW W 1W 2W 3W 4Mp ℃ of H CH 3Cl H OCH 3230-234H I H H OCH 3H H SCH 3H H 177.5-178.5H H OCH 3H CH 3131-135H H F H H 226-228H H Cl H H 217.5-219H H F H OCH 3224-225H H H H SCH 3114.5-115.5H H CH 3H OCH 3201-203H OCH 3H H OCH 3195-196H H H H CH 3145-146H H H H F 181-182H H OCH 3H OCH 3171-172.5H SCH 3H H H 139-140.5H CH 3H CH 3OCH 3CH 3CH 3CH 3H OCH 3H CH (CH 3) 2H H OCH 3H H CH 3CH 3OCH 3H-(CH 2) 3-H OCH 3
Embodiment 6
Preparation 3-methyl-5-nitro-1.2-benzisothiazole
Figure A0080523100551
At-40 ℃, (45g 2.642mmol) leads in the methyl alcohol with ammonia in steel bullet formula reactor.Add then sulphur (30.5g, 95.0mmol) and 2 '-chloro-5 '-nitro-acetophenone (19g, 95.0mmol).With this steel bullet formula reactor sealing, and in about 90 ℃ of heated overnight.After the cooling, reaction mixture is taken out from this steel bullet formula reactor, and vacuum concentration, resistates obtained.Dilute this resistates with methylene dichloride, filter silica gel plug, and vacuum concentration, obtained this title product, be orange solids (12.0g), identify by the NMR spectroscopic analysis.
Use substantially the same method, made following compound:
Figure A0080523100561
Embodiment 7
Preparation 5-amino-3-(the 6-methoxyl group--tolyl)-1, the 2-benzisothiazole
Figure A0080523100562
With 3-(6-methoxyl group--tolyl)-5-nitro-1,2-benzisothiazole (63.0g, 0.210mol), 5% acetate (1.52L, 1.21mol) and the mixture heating up to 65 of ethyl acetate (975mL) ℃, add iron powder (58.6g in batches, 1.05mol), 65 ℃ of stirrings, and filter via quartz filter paper.The separating filtrate phase is used the ethyl acetate extraction water.Organic phase and extraction liquid are merged, and anhydrous magnesium sulfate drying is used in water and salt water washing successively, and vacuum concentration, has obtained this title product, for orange (55.7g, 98.1%), identifies by the NMR spectroscopic analysis.
Use substantially the same method, made following compound: X 5R 40Mp ℃ of H HH CN 118.5-120H CH 3112-113.5H C 2H 5H 179-181H
Figure A0080523100582
90-91F
Figure A0080523100583
H
Figure A0080523100584
130-130.5H 152-153H
Figure A0080523100586
121.5-123H
Figure A0080523100587
108.5-109.5X 5R 40Mp ℃ of H
Figure A0080523100591
158.5-161H
Figure A0080523100592
101.5-102.5H 104-105H
Figure A0080523100594
191-192.5H
Figure A0080523100595
H H
Figure A0080523100597
128-129H
Figure A0080523100598
X 5R 40Mp ℃ of H
Figure A0080523100601
64H 108.5-109.5H 133-134H 114.5-115H
Figure A0080523100605
152-153.5H
Figure A0080523100606
146-147H
Figure A0080523100607
60-65H
Figure A0080523100608
143-145X 5R 40Mp ℃ of H
Figure A0080523100611
100-101H
Figure A0080523100612
H 125-127H
Figure A0080523100614
172-174H 146-147H 161-162H
Figure A0080523100617
173-175X 5R 40Mp ℃ of H
Figure A0080523100621
H H
Figure A0080523100623
H
Embodiment 8
Preparation 3-[3-(6-methoxyl group-3,4-xylyl)-1,2-benzisothiazole-5-yl]-6-(trifluoromethyl)-24 (1H, 3H)-pyrimidine dione
With 5-amino-3-(6-methoxyl group-3,4-xylyl)-1,2-benzisothiazole (8.53g, 30.0mmol), 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazine-6-ketone (6.87g, 33.0mmol) and the mixture of acetate refluxed 2 hours, cooling, and pour in the water.The gained aqueous mixture is filtered, obtained solid.With the solution of this solid in methylene dichloride water successively and salt water washing, use anhydrous magnesium sulfate drying, and vacuum concentration, obtained oily matter.Use silica gel by this oily matter of column chromatography purifying,, obtained this title product,, identify by the NMR spectroscopic analysis for yellow foam (8.37g, 62.0%) with the eluant solution of 5% ether in methylene dichloride.
Use substantially the same method, made following compound:
Figure A0080523100641
X 1X 5R 40Mp ℃ of H H CN 255-258H H H＞260H H CH 3273-274H H C 2H 5H H 230-231H H
Figure A0080523100643
H H
Figure A0080523100644
125-130H H
Figure A0080523100645
＞280H H 253-254X 1X 5R 40Mp ℃ of H H 149-152H H H H
Figure A0080523100653
H H H H
Figure A0080523100655
H H H H
Figure A0080523100657
X 1X 5R 40Mp ℃ of H H
Figure A0080523100661
H H
Figure A0080523100662
H H
Figure A0080523100663
H H 208-210H H
Figure A0080523100665
H H
Figure A0080523100666
X 1X 5R 40Mp ℃ of H H Br F CH 3H F
Figure A0080523100672
PH F CH 3
Embodiment 9
Preparation 3-[3-(tolyl between the 6-methoxyl group)-1,2-benzisothiazole-5-yl]-1-methyl-6-(trifluoromethyl)-2,4 (1H, 3H)-pyrimidine dione
Figure A0080523100673
With 3-[3-(6-methoxyl group--tolyl)-1,2-benzisothiazole-5-yl]-6-(trifluoromethyl)-2,4 (1H, 3H)-pyrimidine dione (160g, 0.369mol), salt of wormwood (76.6g, 0.554mol) and methyl iodide (34.5mL is 0.554mol) at N, mixture in the dinethylformamide is in stirring at room 4 hours, and pours on ice.With dichloromethane extraction gained aqueous mixture.Use the hexane extraction organic extract liquid, wash with water, use anhydrous magnesium sulfate drying, and vacuum concentration, obtained this title product, for orange foam (163g, 98.8%), identify by the NMR spectroscopic analysis.
Use substantially the same method, made following compound:
Figure A0080523100681
X 1X 5Z 3R 40Mp ℃ of H H CH 3H 223-225H H CH 3CN 239-240H H CH 3CH 3244-245H H CH 3CH 2OCH 2CO 2CH 3143-144H H CH 3C 2H 5171-172H H CH 3
Figure A0080523100682
198-200X 1X 5Z 3R 40Mp ℃ of H H CH 3
Figure A0080523100691
170.5-172H H CH 3
Figure A0080523100692
175.5-180H H CH 3
Figure A0080523100693
173-175H H CH 3
Figure A0080523100694
225-227H H CH 3
Figure A0080523100695
185-187H H CH (CH 3) 2
Figure A0080523100696
X 1X 5Z 3R 40Mp ℃ of H H CH 3
Figure A0080523100701
H H CH 3
Figure A0080523100702
187-190H H CH 3
Figure A0080523100703
83-86H H CH 3
Figure A0080523100704
299H H CH 3
Figure A0080523100705
220-225X 1X 5Z 3R 40Mp ℃ of H H CH 3 216-217H H CH 3
Figure A0080523100712
103-105H H CH 2CH 3
Figure A0080523100713
H H C 2H 5
Figure A0080523100714
105-107H H CH 3
Figure A0080523100715
X 1X 5Z 3R 40Mp ℃ of H H CH 3
Figure A0080523100721
H H CH 3 147-149H H CH 3
Figure A0080523100723
170-172H H CH (CH 3) 2
Figure A0080523100724
151-154H H CH 3 H H CH 3
Figure A0080523100726
227-228H F CH 3CH 3X 1X 5Z 3R 40Mp ℃ of H Cl CH 3 Br F CH 3CH 3211-213H F CH 3
Figure A0080523100732
Embodiment 10
Preparation 2-chloro-2 '-methoxyl group-5 '-methyl-5-nitro benzophenone, oxime
(90.0g, 0.294mol) (spend the night, and pour on ice for 102.3g, aqueous solution processing 1.47mol) by backflow with hydroxy amine hydrochloric acid salt for the mixture in ethanol with 2-chloro-2 '-methoxyl group-5 '-methyl-5-nitro benzophenone.The gained aqueous mixture is filtered, obtained solid.Wash this solid with water, and in the vacuum drying oven of heat dried overnight, obtained this title product, be white solid (84.2g), by 1H NMR spectroscopic analysis is identified.
Use substantially the same method, made following compound: X 5W W 2W 3Mp ℃ of H OCH 3H H 173-178H H H H 143-145H H OCH 3H 191-192.5H OCH 3H FH H OCH 2CO 2CH 3H 150-155H OCH 3H CH 3185.5-186.5F OCH 3H CH 3
Embodiment 11
Preparation 3-(the 6-methoxyl group--tolyl)-5-nitro-1, the 2-benzoisoxazole
Figure A0080523100751
With 2-chloro-2 '-methoxyl group-5 '-methyl-5-nitro benzophenone, (84.0g, 0.262mol) mixture in ethanol is warmed to 65 ℃ to oxime, with 25 minutes adding 150mL 10% potassium hydroxide solutions, is heated to 78 ℃, reacts about 1 hour.Cooling, and pour on ice.The gained aqueous mixture is filtered, obtained solid.Wash this solid with water, drying, and use N, the dinethylformamide recrystallization is used N successively, dinethylformamide and washing with alcohol, and in vacuum drying oven in 80 ℃ of dryings, obtained this title compound, be solid (mp225-226 ℃), by 1H NMR spectroscopic analysis is identified.
Use substantially the same method, made following compound:
Figure A0080523100752
X 5W W 2W 3Mp ℃ of H OCH 3H H 170-171H H H H 138-139H H H OCH 3205-207F OCH 3CH 3H
Embodiment 12
Preparation 5-amino-3-(tolyl between the 6-methoxyl group)-1,2-benzoisoxazole and 5-amino-4-chloro-3-(tolyl between the 6-methoxyl group)-1,2-benzoisoxazole
Figure A0080523100761
With 3-(6-methoxyl group--tolyl)-5-nitro-1,2-benzoisoxazole (20.0g, 0.0703mol) mixture in acetate (380mL) is warm, with tin chloride (II) dihydrate (47.4g, 0.210mol) warm solution-treated in concentrated hydrochloric acid (110mL), refluxed 1 hour, be cooled to 10 ℃, and vacuum concentration, obtained jelly.Under agitation this jelly is added in the water, has obtained slurries.60-80 ℃, stir under, in these slurries, add 80g 50% sodium hydroxide solution with 1 hour, cool off, inclining liquid, has obtained resistates.The mixture of this resistates in ethanol handled with potassium hydroxide (10g), and heated overnight is cooled to room temperature, with the hydrochloric acid neutralization, and vacuum concentration, obtained resistates.Dilute this resistates and filtration with ethyl acetate.With the filtrate vacuum concentration, use silica gel by chromatography purification, with the eluant solution of 2% ethyl acetate in methylene dichloride, obtained this title product, be semisolid, identify by ultimate analysis and mass spectroscopy.
Use substantially the same method, but use 5-nitro-3-phenyl-1,2-benzoisoxazole replacement 3-(the 6-methoxyl group--tolyl)-5-nitro-1, the 2-benzoisoxazole has made 5-amino-3-phenyl-1, the 2-benzoisoxazole.
Embodiment 13
Preparation 3-[3-(the 6-methoxyl group--tolyl)-1,2-benzoisoxazole-5-yl]-6-(trifluoromethyl)-2,4 (1H, 3H)-pyrimidine dione
Figure A0080523100771
With 5-amino-3-(6-methoxyl group--tolyl)-1, and the 2-benzoisoxazole (8.40g, 0.033mol), 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazine-6-ketone (7.60g, 0.036mol) mixture with acetate refluxed 3 hours, cooling, pour on ice, and dilute with water.The gained aqueous mixture is filtered, obtained solid.Wash this solid with water, drying has obtained this title product, is pink solid, identifies by the NMR spectroscopic analysis.
Use substantially the same method, made following compound:
Figure A0080523100781
X 1X 5W W 3Mp ℃ of H H OCH 3H 214-216H H H HCl H OCH 3CH 3H F OCH 3CH 3
Embodiment 14
Preparation 3-[3-(the 6-methoxyl group--tolyl)-1,2-benzoisoxazole-5-yl]-1-methyl-6-(trifluoromethyl)-2,4 (1H, 3H)-pyrimidine dione
Figure A0080523100782
With 3-[3-(6-methoxyl group--tolyl)-1,2-benzo Bing oxazole-5-yl]-6-(trifluoromethyl)-2,4 (1H, 3H)-pyrimidine dione (10.5g, 0.0255mol) and salt of wormwood (7.04g, 0.051mol) at N, mixture in the dinethylformamide stirred 15 minutes, and (7.24g 0.051mol) handles with methyl-iodide, stirring is spent the night, and pours on ice.With dichloromethane extraction gained aqueous mixture.Merge organic extract liquid, wash with water, use dried over sodium sulfate, and vacuum concentration, brown glass shape thing obtained.Use silica gel by this glassy mass of dry-column chromatography purifying,, obtained this title product, be pale solid, identify by the NMR spectroscopic analysis with hexane/ethyl acetate solution (3: 1) wash-out.
Use substantially the same method, made following compound: X 1X 5W W 3Mp ℃ of H H OCH 3HH H H H 225-226.5Cl H OCH 3CH 3H F OCH 3CH 3H F OCH 3H
Embodiment 15
Fluorobenzene ester between preparation acetate
With 3-fluorophenol (100g, 0.890mol) solution in methylene dichloride is cooled to 0 ℃-5 ℃, (75.0mL 0.930mol) handles, and stirs several minutes with pyridine, to dripping acetyl chloride (66.0mL wherein, 0.930mol), the temperature with this reaction mixture remains on below 17 ℃ simultaneously, stirs 2 hours in the ice bath temperature, be warmed to room temperature, and pour in the mixture of ice and water.Isolate organic phase, use the salt water washing, use anhydrous magnesium sulfate drying, and vacuum concentration, obtained this title product, be yellow oil, by 1H NMR spectroscopic analysis is identified.
Embodiment 16
Preparation 4 '-fluoro-2 '-hydroxy acetophenone
(123g 0.798mol) cools off in ice bath, and (150g, 1.12mol) batch treatment were stirred 1 hour at 190 ℃, and cooling, had obtained solid with aluminum chloride with fluorobenzene ester between acetate.The mixture and the methylene dichloride that in this solid, add ice, water and hydrochloric acid.The gained mixture is stirred several minutes, separate each phase.With organic phase water successively, saturated sodium bicarbonate solution and salt water washing, use anhydrous magnesium sulfate drying, and vacuum concentration, obtained this title product (99.0g), by 1H NMR spectroscopic analysis is identified.
Embodiment 17
Preparation 4 '-fluoro-2 '-hydroxy acetophenone, oxime
Figure A0080523100802
With 4 '-fluoro-2 '-hydroxy acetophenone (99.0g, 0.640mol), oxammonium hydrochloride (89.0g, 1.28mol) and sodium acetate (79.0g, 0.960mol) mixture in methyl alcohol refluxed 1 hour, and poured in the mixture of ice and water.The gained aqueous mixture is filtered, obtained solid.This solid is dissolved in the methylene dichloride, and with gained organic solution anhydrous magnesium sulfate drying, vacuum concentration with the hexane dilution, and filters, and has obtained this title product, be solid (55.0g, mp112-114 ℃), by 1H NMR spectroscopic analysis is identified.
Embodiment 18
Preparation 6-fluoro-3-methyl isophthalic acid, the 2-benzoisoxazole
Figure A0080523100811
With 4 '-fluoro-2 '-hydroxy acetophenone, oxime (47.0g, 0.278mol) mixture heating up in tetrahydrofuran (THF) is to just refluxing, with 1,1 '-carbonyl dimidazoles (55.0g, 0.340mol) and triethylamine (39.0g, 0.390mol) solution-treated in tetrahydrofuran (THF), refluxed cooling 1 hour, vacuum concentration, and pour in the mixture of ice and water.With extracted with diethyl ether gained aqueous mixture.Merge organic extract liquid, use saturated ammonium chloride solution and salt water washing successively, use anhydrous magnesium sulfate drying, and vacuum concentration, oily matter obtained.Use silica gel by this oily matter of column chromatography purifying,, obtained this title product, be yellow oil with dichloromethane/hexane solution (1: 1) wash-out, by 1H NMR spectroscopic analysis is identified.
Embodiment 19
Preparation 6-fluoro-3-methyl-5-nitro-1, the 2-benzoisoxazole
Figure A0080523100812
With ice bath with 6-fluoro-3-methyl isophthalic acid, 2-benzoisoxazole (23.5g, 0.156mol) cooling of mixture in the vitriol oil, to wherein dripping 90% nitric acid (8.50mL), the temperature with this reaction mixture remains on below 15 ℃ simultaneously, stirs 1 hour in the ice bath temperature, use 90% nitric acid (5.80mL) to handle again, be warmed to room temperature,, and pour on ice in stirred overnight at room temperature.The gained aqueous mixture is filtered, obtained solid.This solid is air-dry, and be dissolved in the diamino methane.With gained organic solution anhydrous magnesium sulfate drying, with the hexane dilution, filter, obtained this title product, be the purple solid, by 1H NMR spectroscopic analysis is identified.
Embodiment 20
Preparation 5-amino-6-fluoro-3-methyl isophthalic acid, 2-benzoisoxazole and 5-amino-4-chloro-6-fluoro-3-methyl isophthalic acid, 2-benzoisoxazole
Figure A0080523100821
With 6-fluoro-3-methyl-5-nitro-1,2-benzoisoxazole (3.00g, 0.0153mol) and the mixture heating up to 40 of acetate (85.0mL) ℃, (9.70g 0.0430mol) and the solution-treated of concentrated hydrochloric acid (45.0mL), refluxed 90 minutes with tin chloride (II) dihydrate, vacuum concentration, with the neutralization of 2N sodium hydroxide solution, filter, obtained solid.Use silica gel by this solid of column chromatography purifying, use the methylene dichloride wash-out, obtained this title product, be solid, identify by the NMR spectroscopic analysis.
Use substantially the same method, but be to use ethyl acetate/alcohol mixture to replace acetate, made following compound:
Figure A0080523100822
X 5R 42H CH 3H ClH OCH 2CO 2CH 3H OCH (CH 3) 2H OCH (CH 3) CO 2CH 3F OCH 2CO 2CH 3H OCH 3
Embodiment 21
Preparation 3-(6-fluoro-3-methyl isophthalic acid, 2-benzoisoxazole-5-yl)-6-(trifluoromethyl)-2,4 (1H, 3H)-pyrimidine dione
Figure A0080523100831
With 5-amino-6-fluoro-3-methyl isophthalic acid, (4.85g is 0.029mol) with 2-dimethylamino-4-(trifluoromethyl)-6H-1 for the 2-benzoisoxazole, 3-oxazine-6-ketone (6.70g, 0.0320mol) mixture in acetate refluxed 90 minutes, and be cooled to room temperature, and pour in the mixture of ice and water.The gained aqueous mixture is filtered, obtained solid.This solid is air-dry, and be dissolved in the ethyl acetate.With the salt water washing of gained organic solution, use anhydrous magnesium sulfate drying, and vacuum concentration, obtained this title product, for yellow solid (7.00g, mp235-237 ℃), identify by the NMR spectroscopic analysis.Use substantially the same method, made following compound:
Figure A0080523100841
X 1X 5R 41Mp ℃ of H H CH 3283-285H H ClH H OCH 2CO 2CH 3180-182H H OCH (CH 3) 2213-215H H OCH 3230-235Cl F CH 3125-130
Embodiment 22
Preparation 3-(6-fluoro-3-methyl isophthalic acid, 2-benzoisoxazole-5-yl)-1-methyl-6-(trifluoromethyl)-2,4 (1H, 3H)-pyrimidine dione
Figure A0080523100842
With 3-(6-fluoro-3-methyl isophthalic acid, 2-benzoisoxazole-5-yl)-6-(trifluoromethyl)-2,4 (1H, 3H)-(3.00 g are 9.12mmol) with salt of wormwood (2.52g for pyrimidine dione, 18.2mmol) at N, mixture in the dinethylformamide stirred 15 minutes, and (2.58g 18.2mmol) handles with methyl-iodide, in stirred overnight at room temperature, and pour in the mixture of ice and water.The gained aqueous mixture is filtered, obtained solid, with this solid recrystallization, obtained this title product,, identify by the NMR spectroscopic analysis for white solid (mp158-159 ℃) with dichloromethane/hexane solution.
Use substantially the same method, made following compound:
Figure A0080523100851
X 1X 5R 41Mp ℃ of H H CH 3196-198H H Cl 168.5-170H H OCH 2CO 2CH 3156-157H H OCH (CH 3) 2H H OCH 3160-161Cl F CH 3154-155
Embodiment 23 preparation 2 '-chloro-5 '-nitro-acetophenones, oxime
Figure A0080523100852
With 2 '-chloro-5 '-nitro-acetophenone (50.0g, the 0.250mol) oxammonium hydrochloride of the mixture in ethanol (83.0g, aqueous solution processing 1.19mol), backflow is spent the night, and is cooled to room temperature, filters, obtained this title product, be solid (mp165-167 ℃), identified by the NMR spectroscopic analysis.
Embodiment 24
Preparation 3-methyl-5-nitro-1, the 2-benzoisoxazole
Figure A0080523100861
With 2 '-chloro-5 '-nitro-acetophenone, oxime (30.0g, 0.140mol) mixture in ethanol drip to be handled with 10% potassium hydroxide solution (7.86g KOH), and stirring at room 1 hour, backflow was spent the night, cooling, and pour in the water.The gained aqueous mixture is filtered, obtained solid.Use silica gel by this solid of column chromatography purifying, use the methylene dichloride wash-out, obtained this title product, be yellow solid (mp84.5-86.5 ℃), identify by the NMR spectroscopic analysis.
Embodiment 25
Preparation 5-nitro-1,2-benzoisoxazole-3-alcohol
With 1, (19.7g 0.146mol) is added in the vitriol oil 2-benzoisoxazole-3-alcohol in batches.With 70% nitric acid batch treatment gained reaction mixture (11.3mL), stirred 90 minutes, and pour on ice.The gained aqueous mixture is filtered, obtained wax shape mashed prod.With this mashed prod recrystallization, obtained this title product with methanol/water mixture, be solid, identified by the 1HNMR spectroscopic analysis.
Use substantially the same method, made following compound:
X 5
Cl
F
Embodiment 26
Preparation [(5-nitro-1,2-benzoisoxazole-3-yl) oxygen base] methyl acetate
With 5-nitro-1,2-benzoisoxazole-3-alcohol (3.90g, 0.0220mol) and salt of wormwood (4.17g, 0.0300mol) at N, mixture in the dinethylformamide stirred 30 minutes, and (3.96g 0.0260mol) handles with methyl bromoacetate, in stirred overnight at room temperature, and pour in the acid mixture of ice and water.With ethyl acetate extraction gained aqueous mixture.Merge organic extract liquid, anhydrous magnesium sulfate drying is used in water and salt water washing successively, and vacuum concentration, has obtained yellow oil.Use silica gel by this oily matter of column chromatography purifying, carry out gradient elution, obtained this title product,, identify by the NMR spectroscopic analysis for white solid (2.80g, mp72-73.5 ℃) with (1: 1)-(4: 1) dichloromethane/hexane.
Use substantially the same method, made following compound:
Figure A0080523100881
X 5R 41Mp ℃ of H OCH (CH 3) 281-83H OCH 2CH=CH 270-72H OCH 3101.5-103Cl OCH (CH 3) CO 2CH 398-100F OCH 2CO 2CH 3104-106
Embodiment 27
Preparation 3-chloro-5-nitro-1, the 2-benzoisoxazole
Figure A0080523100882
With 5-nitro-1,2-benzoisoxazole-3-alcohol (4.00g, 0.0220mol) and phosphorus oxychloride (40.0mL, 65.8g mixture 0.429mol) placed glass bullet formula reactor, 150-155 ℃ of heating 2 hours, cool overnight, vacuum concentration with the methylene dichloride dilution, is adjusted to about pH8 with sodium hydrogen carbonate solution.Separate each phase.With organic phase water successively and salt water washing, use anhydrous magnesium sulfate drying, vacuum concentration has obtained resistates.Use silica gel by this resistates of column chromatography purifying,, obtained this title product, be amber oily thing, identify by the NMR spectroscopic analysis with dichloromethane/hexane solution (1: 1) wash-out.
Embodiment 28
Preparation 2-chloro-2 '-methoxyl group-5-nitro benzophenone
Figure A0080523100891
With 2-bromoanisole (27.9g, 145mmol) solution in ether is cooled to-70 ℃, (64.0mL 160mmol) handles, and stirs 1 hour at-70 ℃ with butyllithium, with the solution (320mL of 0.5M zinc chloride in tetrahydrofuran (THF), 160mmol) handle, stirred 1 hour, be warmed to about 0 ℃ at-70 ℃, and vacuum concentration, obtained yellow-green colour oily matter.The solution of this oily matter in tetrahydrofuran (THF) is used tetrakis triphenylphosphine palladium (0) successively, and (5.00g, 4.35mmol) (35.0g, tetrahydrofuran solution 159mmol) is handled, and stirs 3 days, and pours in 10% hydrochloric acid with 2-chloro-5-nitrobenzoyl chloride.With dichloromethane extraction gained aqueous mixture.Merge organic extract liquid, anhydrous magnesium sulfate drying is used in water and salt water washing successively, and vacuum concentration has obtained semisolid.Develop this solid with ether, obtained this title product, be yellow solid, identify by the NMR spectroscopic analysis.
Use substantially the same method, made following compound: W 1W 2W 3W 4Mp ℃ of H Cl H OCH 396-99H H CH 3OCH 371-74F H H OCH 3Cl H H OCH 3124-126OCH 3H H OCH 371-73H OCH 3H OCH 398-100H F H OCH 3H H CH 3H 65-66.5H H SCH 3H 87-88H H H F 118-120H H H CH 378-79.5H H H SCH 3123-124.5H F H HH H OCH 3HH H H OCH 3H CH 3CH 3OCH 3
Embodiment 29
Preparation 2-chloro-2 '-methoxyl group-5-nitro diphenyl-carbinol
Figure A0080523100911
(50.0g, 0.267mol) solution in ether is added to magnesium in batches (7.10g is 0.293mol) in the mixture in ether with the 2-bromoanisole.After adding fully, with this reaction mixture reflux 1 hour, dilute with ether, be cooled to 0 ℃, with 2-chloro-5-nitrobenzaldehyde (39.0g, 0.210mol) solution-treated in tetrahydrofuran (THF), and dilute with mixture of ice and water, with this water mixture acidifying (pH2-pH3), isolate organic phase with hydrochloric acid then, and use the extracted with diethyl ether water.Merge organic extract liquid, use 10% sodium hydrogen carbonate solution and salt water washing successively, use anhydrous sodium sulfate drying, vacuum concentration has obtained this title product, is brown jelly.
Use substantially the same method, made following compound:
Figure A0080523100912
W???????W 3?????W 4
OCH 3???H???????OCH 3
CH 3????H???????OCH 3
F???????H???????OCH 3
H???????OCH 3???H
Embodiment 30
Preparation 2-chloro-2 '-methoxyl group-5-nitro benzophenone
With chromic oxide (VI) (91.0g, 0.919mol) solution in water/acetic acid solution (1: 4) be added in batches 2-chloro-2 '-methoxyl group-5-nitro diphenyl-carbinol (64.2g, 0.219mol) in, the temperature with this reaction mixture remains on 25 ℃-35 ℃ simultaneously.Then this reaction mixture was stirred 1 hour at 25 ℃-35 ℃, cooling, dilute with water, and vacuum concentration have obtained resistates.With this residue diluted with water, and use dichloromethane extraction.Merge organic extract liquid, use anhydrous sodium sulfate drying, (10g) mixes with silica gel, and filters.With the filtrate vacuum concentration, obtained oily matter.With the solution carbon decoloring of this oily matter in methanol/water solution, vacuum concentration has obtained resistates.Use silica gel by this resistates of column chromatography purifying, use the dichloromethane/hexane eluant solution, obtained this title product, be white solid.
Use substantially the same method, made following compound:
Figure A0080523100922
W 1W 3W 4Mp ℃ of OCH 3H OCH 3CH 3H OCH 3109-111F H OCH 394-95H OCH 3H 79-81
Embodiment 31
Preparation 2-chloro-4-fluoro-5-nitrobenzoyl chloride
Figure A0080523100931
With 2-chloro-4-fluoro-5-nitrobenzoic acid (50.0g, 0.228mol) and N, dinethylformamide (5) is 1, and (30.8mL 0.353mol) drips processing to the mixture in the 2-ethylene dichloride with oxalyl chloride, refluxed 3 hours, cooling, and vacuum concentration have obtained this title product, be orange solids, identify by the NMR spectroscopic analysis.
Embodiment 32
Preparation 2 '-chloro-4 '-fluoro-5 '-nitro-acetophenone
Figure A0080523100932
With the solution (5.00mL of 2M methyl chloride zinc in tetrahydrofuran (THF), 10.1mmol) usefulness 2-chloro-4-fluoro-5-nitrobenzoyl chloride (2.00g, 8.40mmol) solution in tetrahydrofuran (THF) drips and handle, with tetrakis triphenylphosphine palladium (0) (0.400g, 0.350mmol) handle, stirring at room 1 hour, pour in the 3N hydrochloric acid.With ethyl acetate extraction gained aqueous mixture.Merge organic extract liquid, anhydrous magnesium sulfate drying is used in water and saturated sodium bicarbonate solution washing successively, and vacuum concentration, has obtained adopting dark liquid.Use silica gel by the flash column chromatography purifying,, obtained this title product,, identify by the NMR spectroscopic analysis for pale solid (mp66-68 ℃) with solution (6: the 4) wash-out of methylene dichloride in hexane.
Embodiment 33
Preparation 6-amino-3-methyl-5-nitro-1, the 2-benzisothiazole
Figure A0080523100941
With 2 '-chloro-4 '-fluoro-5 '-nitro-acetophenone (12.0g, 0.0552mol), sulphur (1.77g, 0.0552mol), 30% solution of ammonium hydroxide (100mL, 0.856mol) and methanol mixture place steel bullet formula reactor, 85 ℃ of heated overnight, cooling, use sulphur (0.270g) and 30% solution of ammonium hydroxide (50mL) to handle again, 85 ℃ of heated overnight, cooling, the filtering solid, and use ethyl acetate extraction.Merge organic extract liquid, anhydrous magnesium sulfate drying is used in water and salt water washing successively, and vacuum concentration, has obtained solid.Use silica gel by this solid of flash column chromatography purifying,, obtained this title product,, identify by the NMR spectroscopic analysis for orange solids (4.19g, mp189-191 ℃) with the eluant solution of 0%, 1% and 2% ether in methylene dichloride.
Use substantially the same method, made following compound:
Figure A0080523100942
Embodiment 34
Preparation 6-chloro-3-methyl-5-nitro-1, the 2-benzisothiazole
Figure A0080523100951
With nitrite tert-butyl (3.30mL, 0.0278mo1) and cupric chloride (II) (2.98g, 0.0222mol) mixture heating up to 65 in acetonitrile ℃, with 6-amino-3-methyl-5-nitro-1, the 2-benzisothiazole (3.88g, 0.0185mol) batch treatment is 65 ℃ of stirrings, be cooled to room temperature, and pour in 20% hydrochloric acid.With ethyl acetate extraction gained aqueous mixture.Merge organic extract liquid,, use anhydrous magnesium sulfate drying with 20% salt acid elution, and vacuum concentration, solid obtained.Use silica gel by this solid of flash column chromatography purifying,, obtained this title product,, identify by the NMR spectroscopic analysis for yellow solid (2.54g, mp156-158 ℃) with dichloromethane/hexane solution (1: 1 and 3: 1) wash-out.Use substantially the same method, made following compound:
Figure A0080523100952
Embodiment 35
Preparation 6-fluoro-3-methyl-5-nitro-1, the 2-benzisothiazole
Figure A0080523100953
With 6-chloro-3-methyl-5-nitro-1,2-benzisothiazole (2.25g, 9.80mmol), Potassium monofluoride (2.85g, 49.0mmol) and 18-hat-6 (1.50g, 5.70mmol) mixture in acetonitrile heated in sealed tube 29 days, the filtering solid, and concentrated in the vacuum lower section, obtained liquid.This liquid is diluted with ethyl acetate, and anhydrous magnesium sulfate drying is used in water and salt water washing successively, and vacuum concentration has obtained dark brown solid.Use silica gel by this solid of flash column chromatography purifying, carry out gradient elution, obtained to contain the yellow solid of two kinds of components with the solution of 10%-50% ethyl acetate in hexane.Use silica gel by this yellow solid of flash column chromatography purifying, carry out gradient elution, obtained this title product,, identify by the NMR spectroscopic analysis for yellow solid (0.870g, mp118-119 ℃) with the solution of 50%-70% ethyl acetate in hexane.Use substantially the same method, made following compound:
Figure A0080523100961
Embodiment 36
Preparation 5-amino-6-fluoro-3-methyl isophthalic acid, the 2-benzisothiazole
Figure A0080523100962
With 6-fluoro-3-methyl-5-nitro-1, and the 2-benzisothiazole (0.740g, 3.50mmol), the solution of 5% acetate (25.0mL) and ethyl acetate is heated to 65 ℃, (0.980g 17.5mmol) handles, and stirs 1 hour at 65 ℃ with iron powder, be cooled to room temperature, and the filtering solid.Isolate organic phase, anhydrous magnesium sulfate drying is used in water, saturated sodium bicarbonate solution and salt water washing successively, and vacuum concentration, has obtained this title product, is orange solids (0.610g), identifies by the NMR spectroscopic analysis.
Use substantially the same method, made following compound:
Embodiment 37
Preparation 2-chloro-4-fluoro-5-nitro benzophenone
With 2-chloro-4-fluoro-5-nitrobenzoyl chloride (26.7g, 0.112mol) and benzene (12.0mL is 0.134mol) 1,1,2, the solution in the 2-tetrachloroethane is cooled to 0 ℃-5 ℃, with aluminum chloride (18.1g, 0.136mol) handle, stirred 15 minutes at about 8 ℃, be heated to 50 ℃, and under this temperature, stirred 1 hour, be cooled to room temperature, successively with mixture of ice and water and concentrated hydrochloric acid dilution.Isolate organic phase, anhydrous magnesium sulfate drying is used in water and saturated sodium bicarbonate solution washing successively, and vacuum concentration has obtained solid.Use silica gel by this solid of flash column chromatography purifying, use the methylene dichloride wash-out, obtained this title product, be orange solids (30.8g), identify by the NMR spectroscopic analysis.
Embodiment 38
Preparation 2,2 '-dithio two [5-nitrobenzoic acid]
Figure A0080523100981
With 2-chloro-5-nitrobenzoic acid (100g, 0.496mol) mixture in ethanol is with potassium tert.-butoxide (55.5g, 0.495mol) batch treatment, with other alcohol dilution, be heated to backflow, add in batches with the sodium sulphite nonahydrate (60.0g, 0.249mol), sulphur (8.80g, 0.274mol) and the solution that makes of water, and handle with concentrated hydrochloric acid.The gained acidic mixture was stirred 1 hour, filter, obtained solid.Wash this solid with water, air-dry, obtained this title product, be yellow powder, identify by the NMR spectroscopic analysis.
Embodiment 39
Preparation 5-nitro-1,2-benzisothiazole-3 (2H)-ketone
Figure A0080523100982
With 2, and 2 '-dithio-two [5-nitrobenzoic acid] (44.6g, 0.113mol) and thionyl chloride (49.0mL, 0.670mol) mixture N in methylene dichloride, dinethylformamide (0.800mL) is handled, and backflow is spent the night, vacuum concentration, and with 1, the dilution of 2-ethylene dichloride.(22.5mL 0.436mol) handles gained organic solution, stirring at room 20 minutes, refluxes 3.5 hours, and vacuum concentration has obtained resistates with bromine.With ice-water bath with this resistates 1, the cooling of solution in the 2-ethylene dichloride with adding strong aqua (112mL) in 15 minutes, stirring at room 16 hours, is cooled off with ice-water bath, and is handled with concentrated hydrochloric acid.The gained aqueous mixture stirring at room 1 hour, is filtered, obtained solid.Wash this solid with water, air-dry, obtained this title product, be yellow solid, identify by the NMR spectroscopic analysis.
Embodiment 40
Preparation 3-chloro-5-nitro-1, the 2-benzisothiazole
Figure A0080523100991
With 5-nitro-1, and 2-benzisothiazole-3 (2H)-ketone (10.0g, 0.0510mol), phosphorus oxychloride (40.0mL, 0.429mol) and tributylamine (12.0mL, 0.050mol) 103-115 ℃ of heating 6 hours, in stirred overnight at room temperature, and pour in the mixture of ice and water.With dichloromethane extraction gained aqueous mixture.Merge organic extract liquid, anhydrous sodium sulfate drying is used in water and saturated sodium bicarbonate solution washing successively, and vacuum concentration has obtained jelly.Use silica gel by this jelly of column chromatography purifying, use the methylene dichloride wash-out, obtained title product, be orange/yellow solid, identify by the NMR spectroscopic analysis.
Embodiment 41
Preparation alpha-cyano-5-nitro-1,2-benzisothiazole-3-ethyl acetate
Figure A0080523101001
With ice-acetone bath just alcohol sodium solution (use ethanol and sodium (1.00g in advance, 0.0430mol) preparation) cooling, add in batches ethyl cyanacetate (4.51g, 0.0398mol), stirring at room 30 minutes, add 3-chloro-5-nitro-1, the 2-benzisothiazole (4.27g, 0.0199mol), in stirred overnight at room temperature, be cooled to 0 ℃, drip 10% hydrochloric acid (15.0mL).The gained aqueous mixture stirring at room 1 hour, is filtered, obtained solid.With this solid of washing with alcohol, air-dry, obtained this title product, be yellow solid, identify by the NMR spectroscopic analysis.
Embodiment 42
Preparation 5-nitro-1,2-benzisothiazole-3-ethyl acetate
Figure A0080523101002
With alpha-cyano-5-nitro-1, (6.67g 0.0229mol) is added in the solution of Acetyl Chloride 98Min. (67.0mL) in ethanol 2-benzisothiazole-3-ethyl acetate.This reaction mixture refluxed is spent the night cooling, and filtering solid.With gained filtrate vacuum concentration, obtained brown semisolid.The mixture of this semisolid in ether stirred 2 hours, filter, obtained solid.Wash this solid with ether, air-dry, obtained this title product, be yellow crystals (1.04g, mp91-92 ℃).
Embodiment 43
Preparation 5-amino-1,2-benzisothiazole-3-ethyl acetate
With 10% acetic acid solution (31.0mL) 50 ℃ of stirrings, handle with iron powder (0.656g), Dropwise 5-nitro-1,2-benzisothiazole-3-ethyl acetate (1.03g, 3.88mmol the solution in ethyl acetate stirred 2 hours at 50 ℃, used iron powder (0.305g) to handle again, stirred 15 minutes at 50 ℃, pour in the saturated sodium bicarbonate solution.In ethyl acetate extraction gained aqueous mixture.Merge organic extract liquid, anhydrous sodium sulfate drying is used in water and salt water washing successively, and vacuum concentration has obtained oily matter.Use silica gel by this oily matter of column chromatography purifying, use the methylene dichloride wash-out, obtained this title product, be yellow oil.
Embodiment 44
Preparation 5-[3,6-dihydro-2,6-dioxo-4-(trifluoromethyl)-1 (2H)-pyrimidyl]-1,2-benzisothiazole-3-ethyl acetate
Figure A0080523101021
With 5-amino-1, (0.748g is 3.16mmol) with 2-dimethylamino-4 (trifluoromethyl)-6H-1 for 2-benzisothiazole-3-ethyl acetate, 3-oxazine-6-ketone (0.660g, 3.17mmol) mixture in acetate refluxed 3 hours, vacuum concentration dilutes with saturated sodium bicarbonate solution.With dichloromethane extraction gained mixture.The organic extract liquid that merges is washed with water, use anhydrous sodium sulfate drying, and vacuum concentration, obtained this title compound, be the tawny solid, identify by the NMR spectroscopic analysis.
Embodiment 45
Preparation 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1 (2H)-pyrimidyl]-1,2-benzisothiazole-3-ethyl acetate
With 5-[3,6-dihydro-2,6-dioxo-4-(trifluoromethyl)-1 (2H)-pyrimidyl]-1,2-benzisothiazole-3-ethyl acetate (0.643g, 0.00160mol) and salt of wormwood (0.243g, 0.00170mol) at N, mixture in the dinethylformamide was stirring at room 90 minutes, and (0.320mL 0.00500mol) handles with methyl iodide, in stirred overnight at room temperature, and dilute with water.With dichloromethane extraction gained aqueous mixture.Organic extract liquid is washed with water, use anhydrous magnesium sulfate drying, and vacuum concentration, brown oil obtained.Use silica gel by this oily matter of column chromatography purifying,, obtained this title product, be tawny solid (0.362g, mp150-152 ℃) with the eluant solution of 10% ethyl acetate in hexane.
Embodiment 46
Preparation 5-nitro-1,2-benzisothiazole-3-acetonitrile
With 5-nitro-1, (5.00g 17.2mmol), the mixture of water (1.00mL) and methyl-sulphoxide (35.0mL) stirred 24 hours at 107 ℃, stirring at room 2 days, pours in the mixture of ice and water 2-benzisothiazole-3-ethyl acetate.The gained aqueous mixture was stirred 2 hours, filter, obtained solid.Water is with this solids wash, and is air-dry, obtained this title product, is the tawny solid.
Embodiment 47
Preparation α, alpha-alpha-dimethyl-5-nitro-1,2-benzisothiazole-3-acetonitrile
With 5-nitro-1,2-benzisothiazole-3-acetonitrile (1.29g, 5.89mmol) at N, mixture in the dinethylformamide is cooled to-9 ℃, handle with sodium hydride (1.00g 60% mineral oil dispersion liquid), stirred 20 minutes, handle with methyl iodide (5.00mL) at-3 ℃, stirring at room 4 hours, and pour on ice.The gained aqueous mixture with 10% salt acid treatment, and is used dichloromethane extraction.Merge organic extract liquid, anhydrous sodium sulfate drying is used in water, saturated sodium bicarbonate solution and water washing successively, and vacuum concentration, has obtained solid.Use silica gel by this solid of column chromatography purifying, use the methylene dichloride wash-out, obtained this title product, be yellow solid, identify by the NMR spectroscopic analysis.
Embodiment 48
Preparation α, alpha-alpha-dimethyl-5-nitro-1,2-benzisothiazole-3-ethyl acetate
Figure A0080523101042
With α, alpha-alpha-dimethyl-5-nitro-1,2-benzisothiazole-3-acetonitrile (0.913g, 3.69mmol), the mixture of water (0.450mL), the vitriol oil (4.55mL) and ethanol (9.10mL) refluxed 1 hour, cooling, and pour on ice.With saturated sodium bicarbonate solution the gained aqueous mixture is neutralized, and use dichloromethane extraction.Wash organic extract with water, use anhydrous sodium sulfate drying, vacuum concentration has obtained solid.Use silica gel by this solid of column chromatography purifying, use the methylene dichloride wash-out, obtained this title product, be pale yellow crystals.
Embodiment 49
Preparation 5-oxygen base-α, alpha-alpha-dimethyl-1,2-benzisothiazole-3-ethyl acetate
Figure A0080523101051
With α, alpha-alpha-dimethyl-5-nitro-1, and 2-benzisothiazole-3-ethyl acetate (0.714g, 2.42mmol), the mixture of iron powder (0.500g), 10% acetate (23.0mL) and ethyl acetate (23.0mL) stirred 1 hour at 54-58 ℃, cooling, and pour in the saturated sodium bicarbonate solution.With ethyl acetate extraction gained aqueous mixture.Merge organic extract liquid, anhydrous sodium sulfate drying is used in water and salt water washing successively, and vacuum concentration, has obtained yellow oil.Use silica gel by this oily matter of column chromatography purifying,, obtained this title product, be light brown oily thing, identify by the NMR spectroscopic analysis with the eluant solution of 10% ethyl acetate in methylene dichloride.
Embodiment 50
Preparation 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1 (2H)-pyrimidyl]-α, alpha-alpha-dimethyl-1,2-benzisothiazole-3-ethyl acetate
Figure A0080523101061
With 5-amino-α, alpha-alpha-dimethyl-1,2-benzisothiazole-3-ethyl acetate (0.546g, 2.06mmol) and 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazine-6-ketone (0.430g, 2.06mmol) mixture in acetate refluxed 4.5 hours, vacuum concentration, and dilute with saturated sodium bicarbonate solution.With dichloromethane extraction gained aqueous mixture.Merge organic extract liquid, wash with water, use anhydrous sodium sulfate drying, vacuum concentration has obtained brown foam.At N, (0.312g 2.25mmol) handles the solution in the dinethylformamide with salt of wormwood with this foam, stirred 1 hour, (0.420mL 6.70mmol) handles with methyl iodide, in stirred overnight at room temperature, pour in the mixture of ice and water that contains the 20mL concentrated hydrochloric acid.With dichloromethane extraction gained aqueous mixture.Merge organic extract liquid, use 10% hydrochloric acid, water, saturated sodium bicarbonate solution and water washing successively, use anhydrous sodium sulfate drying, and vacuum concentration, brown oil obtained.Use silica gel by this oily matter of column chromatography purifying,, obtained pink foam, with its recrystallization, obtained this title product, be pink crystal, mp164-167 ℃ with ethanol with the eluant solution of 33% ethyl acetate in methylene dichloride.
Embodiment 51
Preparation 5-amino-3-chloro-1, the 2-benzisothiazole
With 3-chloro-5-nitro-1, the solution of 2-benzisothiazole (2.00g) in toluene iron powder (8.40g, 325 orders) and concentrated hydrochloric acid (8) handle, be heated to backflow,, refluxed 35 minutes to wherein dripping water (8.00mL), be cooled to room temperature, via diatomite filtration,, obtained resistates with gained filtrate vacuum concentration.Use silica gel by this resistates of flash column chromatography purifying,, obtained this title product with ethyl acetate/hexane solution (1: 1) wash-out.
Embodiment 52
Preparation 3-(3-chloro-1,2-benzisothiazole-5-yl)-6-(trifluoromethyl)-2,4 (1H, 3H)-pyrimidine dione
With 5-amino-3-chloro-1,2-benzisothiazole (1.10g) and 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazine-the mixture of 6-ketone (1.38g) in acetate (15.1mL) stirred 2 hours at 90-105 ℃, be cooled to room temperature, filter, obtain this title product of 0.500g, be solid.With the dilution of gained filtrate water, filter, obtained this title product of 1.11g again.
Embodiment 53
Preparation 3-(3-chloro-1,2-benzisothiazole-5-yl)-1-methyl-6-(trifluoromethyl)-2.4 (1H, 3H)-pyrimidine dione
Figure A0080523101081
With 3-(3-chloro-1,2-benzisothiazole-5-yl)-6-(trifluoromethyl)-2,4 (1H, 3H)-pyrimidine dione (1.06g), salt of wormwood (0.470g) and methyl iodide (0.500mL) be at N, mixture in the dinethylformamide was in stirring at room 90 minutes, use methyl iodide (0.500mL) to handle again, stirring at room 15 minutes, and dilute with water.The gained aqueous mixture is filtered, obtained solid.This solid is washed with water, and in vacuum drying oven in drying at room temperature, obtained this title product, be solid, identify by the NMR spectroscopic analysis.
Embodiment 54
Preparation [(5-nitro-1,2-benzisothiazole-3-yl) oxygen base] acetonitrile
With 5-nitro-1,2-benzisothiazole-3 (2H)-ketone (17.5g, 89.2mmol) at N, (18.5g 134mmol) handled, stirring at room 30 minutes with salt of wormwood for mixture in the dinethylformamide, with bromoacetonitrile (16.0g, 133mmol) handle,, and pour on ice in stirred overnight at room temperature.With hydrochloric acid the gained aqueous mixture is acidified to pH3, and uses ethyl acetate extraction.Merge organic extract liquid, anhydrous magnesium sulfate drying is used in water and salt water washing successively, and vacuum-drying has obtained solid.Use silica gel by this solid of column chromatography purifying, use the methylene dichloride wash-out, obtained this title product, be yellow solid (15.0g, mp123-124.5 ℃).
Use substantially the same method, made following compound:
Figure A0080523101092
R 40Mp ℃ of OCH 3108-109OCH (CH 3) 2OCH 2CH=CH 2OCH 2C ≡ CH 115-117OCH 2CO 2CH 3
Embodiment 55
Preparation [(5-amino-1,2-benzisothiazole-3-yl) oxygen base] acetonitrile
Figure A0080523101101
With iron powder (13.0g, 0.233mol) mixture heating up to 50 in 5% acetic acid solution (65.0mL) ℃, add [(5-nitro-1 in batches, 2-benzisothiazole-3-yl) oxygen base] acetonitrile (11.0g, 0.047mol), the mixture of acetate (100mL) and ethyl acetate (65.0mL), refluxed 2 hours, and be cooled to 40 ℃, the filtering solid.Separate each phase, use the ethyl acetate extraction water.Organic phase and organic extract are merged, and anhydrous magnesium sulfate drying is used in water and salt water washing successively, and vacuum concentration has obtained this title product, is oily matter, identifies by the NMR spectroscopic analysis.
Use substantially the same method, made following compound:
Figure A0080523101102
R 40
OCH 3
OCH(CH 3) 2
OCH 2CH＝CH 2
OCH 2C≡CH
OCH 2CO 2CH 3
Embodiment 56
Preparation 5-[3,6-dihydro-2,6-dioxo-4-(trifluoromethyl)-1 (2H)-pyrimidyl] and-1,2-benzisothiazole-3-yl } the oxygen base } acetonitrile
Figure A0080523101111
(4.30g is 21.0mmol) with 2-dimethylamino-4-(trifluoromethyl)-6H-1 with [(5-amino-1,2-benzisothiazole-3-yl) oxygen base] acetonitrile, 3-oxazine-6-ketone (4.37g, 21.0mmol) mixture in acetate refluxed 3 hours, and in stirred overnight at room temperature, poured in the mixture of ice and water.The gained aqueous mixture is filtered, obtained solid.Wash this solid with water, in vacuum drying oven,, obtained this title product, be brown solid (2.63g, mp254-258 ℃) in 55 ℃ of dried overnight.
Use substantially the same method, made following compound:
Figure A0080523101112
R 40???????????????mp℃
OCH 3
OCH(CH 3) 2????????180-185
OCH 2CH＝CH 2??????210-212
OCH 2C≡CH?????????212-215
OCH 2CO 2CH 3
Embodiment 57
Preparation 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1 (2H)-pyrimidyl] and-1,2-benzisothiazole-3-yl } the oxygen base } acetonitrile
Figure A0080523101121
With { { 5-[3,6-dihydro-2,6-dioxo-4-(trifluoromethyl)-1 (2H)-pyrimidyl]-1,2-benzisothiazole-3-yl } the oxygen base } acetonitrile (2.63g, 7.15mmol) and salt of wormwood (1.97g, 14.3mmol) at N, mixture in the dinethylformamide stirred 30 minutes, and (2.03g 14.3mmol) handles with methyl iodide, in stirred overnight at room temperature, and pour in the mixture of ice and water.The gained aqueous mixture is filtered, obtained solid.This solid is dissolved in the ethyl acetate, with gained solution water successively and salt water washing, uses anhydrous magnesium sulfate drying, vacuum concentration has obtained brown solid.Use silica gel by this solid of column chromatography purifying, use the methylene dichloride wash-out, obtained yellow solid.With this yellow solid recrystallization, obtained this title product with dichloromethane/hexane solution, be pale solid, mp265-266 ℃.
Use substantially the same method, made following compound:
R 40?????????????mp℃
OCH 3????????????198-199
OCH(CH 3) 2??????125-127
OCH 2CH＝CH 2????184-185
OCH 2C≡CH???????201-202.5
OCH 2CO 2CH 3????181-183
Embodiment 58
Preparation 5-nitro-1, the 2-benzisothiazole
Figure A0080523101132
To ammonium hydroxide (1000ml) and N, add in the mixture of dinethylformamide 2-chloro-5-nitrobenzaldehyde (300g, 1.62mol) and sulphur (54.4g, 1.70mol).This mixture is heated to 90 ℃ lentamente, and under this temperature, stirred 1 hour, be cooled to room temperature, pour on ice, and dilute with water.Filter, obtained this title compound, be yellow solid (277.1g, 94.9%).
Embodiment 59
Preparation 3-chloro-5-nitro-1, the 2-benzisothiazole
With 5-nitro-1, (271g, 1.50mol) suspension in acetate is heated to 80 ℃ to the 2-benzisothiazole, to form solution.Remove heating source, it is saturated until this mixture to continue logical 6 hours chlorine at 70-80 ℃.This mixture is cooled to room temperature, and stirs and spend the night.Filter, obtained this title compound,, identify by the NMR spectroscopic analysis for yellow solid crystallization (237g, 73.6%).
Embodiment 60
Preparation 2 '-chloro-2-methyl-2-ethoxycarbonyl Propiophenone
Figure A0080523101142
With 2-chloro-benzoyl chloride (52.2g, 0.298mol), the 2-isobutyl ethyl bromide (58.2g, 0.298mol) and the mixture of ether be added in batches the zinc paper tinsel (19.5g, 0.298mol) in, the gained mixture was stirred 3 hours under reflux state, and in stirred overnight at room temperature.This mixture is poured in the cold dilute sulphuric acid, with saturated sodium bicarbonate and salt water washing organic layer, used anhydrous magnesium sulfate drying, vacuum concentration has obtained yellow oil.By this oily matter of silica gel chromatography purifying, use hexane: eluent ethyl acetate, obtained this title compound, be colorless oil (41.8g, 55.1%).
Embodiment 61
Preparation 2 '-chloro-5 '-nitro-2-methyl-2-ethoxycarbonyl Propiophenone
At 5 ℃, in the vitriol oil (15.0ml), add 2 '-chloro-2-methyl-2-ethoxycarbonyl Propiophenone (4.00g, 0.01570mol), drip then concentrated nitric acid (90%, 0.740ml, 0.0204mol).Stir after 5 minutes, this mixture is poured on ice, and used ethyl acetate extraction.With saturated sodium bicarbonate and salt water washing organic layer, use anhydrous magnesium sulfate drying, filter and vacuum concentration, obtained this title compound, for yellow oil (3.90g, 83.0%), identify by the NMR spectroscopic analysis.
Embodiment 62
Preparation α, alpha-alpha-dimethyl-5-nitro-1,2-benzisothiazole-3-ethyl acetate
To 2 '-chloro-5 '-nitro-2-methyl-2-ethoxycarbonyl Propiophenone (3.24g, 0.00108mol), N, dinethylformamide and sulphur (0.350g, 0.00109mol) mixture in drip ammonium hydroxide (9ml), be heated to 70-80 ℃, and under this temperature, stirred 2 hours, be cooled to room temperature, and dilute with water.Filter, obtained this title compound,, identify by the NMR spectroscopic analysis for solid (2.49g, 78.3%, mp75-77 ℃).
Embodiment 63
Preparation 1-thionaphthene-2, the 3-diketone
Figure A0080523101161
(100g 0.907mol) drips oxalyl chloride (175g, diethyl ether solution 1.38mol) in the solution in ether to thiophenol.This mixture was stirred 2 hours under reflux state, and vacuum concentration.Resistates is placed methylene dichloride, and be cooled to 0 ℃.Add in batches aluminum chloride (145g, 1.09mol) so that temperature is no more than 25 ℃.The gained mixture was stirred 30 minutes under reflux state, be cooled to room temperature, and under agitation pour in the frozen water.Organic layer with saturated sodium bicarbonate, water and salt water washing, is used anhydrous magnesium sulfate drying, filter and vacuum concentration, obtained orange solids, used methylene dichloride: hexane has obtained this title compound (102g with its recrystallization, 69.0%), identifies by the NMR spectroscopic analysis.
Embodiment 64
Preparation 1,2-benzisothiazole-3-methane amide
At 5-10 ℃, in ammonium hydroxide (1.781), add 1-thionaphthene-2, the 3-diketone (87.0g, 0.530mol), add then hydrogen peroxide (30% aqueous solution, 178ml).The gained mixture is filtered, obtained yellow solid, dry (77.0g, 81.7%) has identified that by NMR and IR spectroscopic analysis it is this title compound.
Embodiment 65
Preparation 3-cyano group-5-nitro-1, the 2-benzisothiazole
At 0-5 ℃, to 1,2-benzisothiazole-3-methane amide (12.0g, 0.0674mol) drip in the solution in the vitriol oil nitric acid (90%, 4.12ml) so that temperature is no more than 10 ℃, stirred 1 hour at 5 ℃, and under vigorous stirring, pour in the frozen water.With the gained suspension filtered, obtained solid.With this solid drying, and use the acetonitrile recrystallization, obtained white solid (10.0g), handle with phosphorus oxychloride (60.0ml).The gained mixture was stirred 90 minutes at 90-100 ℃, be cooled to room temperature, under agitation pour into lentamente in the frozen water, filter, obtained solid.Use methylene dichloride: hexane has obtained this title compound with this solid recrystallization, is orange solids (8.00g, 87.9%, mp168-170 ℃), identifies by NMR and IR spectroscopic analysis.
Embodiment 66
Preparation 2,4-two fluoro-5-nitrobenzoyl chlorides
With oxalyl chloride (94.0g 0.739mo1) is added drop-wise to 2,4-two fluoro-5-nitrobenzoic acids (100.0g, 0.492mol), methylene dichloride and N, in the mixture of N dimethyl formamide (0.600ml).The gained mixture was stirred 3.25 hours under reflux state, be cooled to room temperature, and vacuum concentration, obtained this title compound, be brown oil (111g, 95.2%).
Embodiment 67
Preparation 2 ', 4 '-difluoro-2-methoxyl-5-methyl-5 '-nitro benzophenone
With aluminum chloride (62.3g, 0.467mol) be cooled to-20 ℃ with the mixture of methylene dichloride--10 ℃, (60.1g 0.492mol) handles, and wherein drips 2 with 10 fens clockwise with 4-methylbenzene methyl ether, 4-two fluoro-5-nitrobenzoyl chloride (111g, 0.468mol) with the mixture of methylene dichloride, temperature is risen to 0 ℃, in stirred overnight at room temperature, under agitation pour on ice lentamente, and dilute with methylene dichloride.With organic layer water and salt water washing, use anhydrous magnesium sulfate drying, and vacuum concentration, obtained solid.With this solid recrystallization, obtained this title compound with acetonitrile,, identified by the NMR spectroscopic analysis for yellow solid (82.1g, 54.0%).
Embodiment 68
Preparation 3-(the 6-methoxyl group--tolyl)-6-amino-5-nitro-1, the 2-benzisothiazole
Under the ice bath cooling conditions, with ammonium hydroxide (330ml) be added to 2 ', 4 '-difluoro-2-methoxyl-5-methyl-5 '-nitro benzophenone (60.0g, 0.186mol), sulphur (6.25g, 0.195mol) and N, in the suspension of dinethylformamide.The gained mixture is warmed to 35 ℃, is heated to 81 ℃ gradually with 2 hours, be cooled to room temperature, and pour in the water.The gained solid is placed ethyl acetate and N, in the dinethylformamide, and wash with water.With the organic layer vacuum concentration, obtained this title compound, identify by the NMR spectroscopic analysis.
Embodiment 69
Preparation 3-(the 6-methoxyl group--tolyl)-6-chloro-5-nitro-1, the 2-benzisothiazole
With nitrite tert-butyl (5.90g, 0.0571mol), cupric chloride (6.20g, 0.0457mol) and the mixture heating up of acetonitrile to 65-75 ℃, with adding 3-(6-methoxyl group--tolyl)-6-amino-5-nitro-1,2-benzisothiazole (12.0g in 10 minutes, 0.0381mol), stirred 2 hours at 67-75 ℃, handle, stirred 40 minutes at 67-75 ℃ with nitrite tert-butyl (1.50ml) and cupric chloride (1.00g), be cooled to room temperature, and dilute with ethyl acetate.Organic layer with 10% salt acid elution, and is filtered.Wash filtrate with water, vacuum concentration has obtained this title compound, is solid (10.6g, 83.1%), identifies by NMR and IR spectroscopic analysis.
Embodiment 70
Preparation 3-(the 6-methoxyl group--tolyl)-6-fluoro-5-nitro-1, the 2-benzisothiazole
Figure A0080523101201
With 3-(6-methoxyl group--tolyl)-6-chloro-5-nitro-1,2-benzisothiazole (7.30g, 0.0218mol), Potassium monofluoride (6.33g, 0.109mol), 18-is preced with-6 (2.31g, 0.0872mol) and the mixture of tetramethylene sulfone stirred 19 hours at 154 ℃, be cooled to room temperature, and pour in the frozen water.Filter out formed solid,, use the methylene dichloride wash-out, obtained solid, use the acetonitrile recrystallization, obtained the tawny powder by the silica gel chromatography purifying.With this powder recrystallization, obtained this title compound with ethyl acetate,, identified by the NMR spectroscopic analysis for tawny solid (2.09g, 29.9%).
Embodiment 71
Preparation 5-amino-4-bromo-6-fluoro-3-methyl isophthalic acid, the 2-benzisothiazole
Figure A0080523101211
To 5-amino-6-fluoro-3-methyl isophthalic acid, (0.600g is 0.00329mol) 1 for the 2-benzisothiazole, add N-bromosuccinimide (0.586g in the solution in 2 ethylene dichloride, 0.00329mol), add 1,1 then '-azo two (hexanaphthene formonitrile HCN) is (0.0200g).This mixture was stirred 2 hours at 70 ℃, and then (0.240g 0.00135mol), and stirs this mixture 40 minutes at 70 ℃ to add N-bromosuccinimide.This mixture is cooled to room temperature, filters and vacuum concentration, obtained resistates.By this resistates of silica gel chromatography purifying, obtained this title compound (0.870g, 100%), identify by the NMR spectroscopic analysis.

Claims (42)

1. (N, N-the is dibasic) amino-4-of 2-shown in the preparation formula I (perfluoroalkyl)-1, the method for 3-oxazine-6-ketone compound
Figure A0080523100021
Wherein Z and Z 1Be C independently respectively 1-C 8Alkyl, perhaps Z and Z 1Form 4-7 unit ring, wherein ZZ1 representative-(CH with the atom that they connected 2) 2O (CH 2) 2-or-(CH 2) m-, wherein m is an integer 3,4,5 or 6; With n be integer 1,2,3,4,5 or 6, described method comprises: (a) make beta-amino-β shown in the formula II-(perfluoroalkyl) acrylate Wherein n as mentioned above, and Z 2Be C 1-C 6Alkyl or benzyl, wherein said benzyl can be chosen wantonly on phenyl ring by 1-3 halogen, C 1-C 4Alkyl or C 1-C 4Haloalkyl replaces, and reacts with carbamyl chlorine compound shown in alkali and the formula III
Figure A0080523100023
Wherein Z and Z 1As mentioned above, to form carbamide compound shown in the formula IV (b) make the reaction of formula IV urea and phosphorus pentahalides or oxalyl halogen.
2. the process of claim 1 wherein that the two keys in formula II and the IV compound mainly are (Z)-configuration.
3. the process of claim 1 wherein that described alkali is selected from alkalimetal hydride, basic metal C 1-C 6Alkoxide, alkali metal hydroxide, alkaline carbonate, alkaline earth metal hydroxides, alkaline earth metal carbonate and lithium alkali.
4. the method for claim 3, wherein said alkali is selected from alkalimetal hydride and basic metal C 1-C 6Alkoxide.
5. the method for claim 4, wherein said alkali is selected from sodium hydride, sodium tert-butoxide and potassium tert.-butoxide.
6. the process of claim 1 wherein that described phosphorus pentahalides is that phosphorus pentachloride and described oxalyl halogen are oxalyl chlorides.
7. the process of claim 1 wherein in the presence of first kind of solvent, make the reaction of beta-amino-β-(perfluoroalkyl) acrylate and alkali and urea chloride, and in the presence of second kind of solvent, make the reaction of urea and phosphorus pentahalides or oxalyl halogen.
8. the method for claim 7, wherein said first kind of solvent is selected from carboxylic acid amide, ether, nitrile and dialkyl sulphoxide and composition thereof; Second kind of solvent is selected from three oxyhalogen phosphorus, aromatic hydrocarbons, halogenated aryl hydrocarbon, carboxylic acid amide, aliphatic hydrocrbon and halogenated aliphatic hydrocarbon and composition thereof.
9. the method for claim 8, wherein said first kind of solvent is N, dinethylformamide.
10. the process of claim 1 wherein that beta-amino-β-(perfluoroalkyl) acrylate and alkali and urea chloride are reacting under-20 ℃ of-80 ℃ of temperature approximately, and urea and phosphorus pentahalides or oxalyl halogen react under about 0 ℃ of-100 ℃ of temperature.
11. the method for claim 10, wherein beta-amino-β-(perfluoroalkyl) acrylate and alkali and urea chloride react under about 0 ℃ of-50 ℃ of temperature, and urea and phosphorus pentahalides or oxalyl halogen react under about 20 ℃ of-50 ℃ of temperature.
12. the process of claim 1 wherein Z and Z 1Be C independently respectively 1-C 6Alkyl; Z 2Be C 1-C 4Alkyl; With n be 1.
13. the method for claim 12, wherein Z and Z 1Identical, and represent methylidene or ethyl; Z 2Be methyl or ethyl; With n be 1.
14. 2-shown in the preparation formula I (N, N-two replaces) amino-4-(perfluoroalkyl)-1, the method for 3-oxazine-6-ketone compound
Figure A0080523100051
Wherein Z and Z 1Be C independently respectively 1-C 8Alkyl, perhaps Z and Z 1Form 4-7 unit ring, wherein ZZ with the atom that they connected 1By-(CH 2) 2O (CH 2) 2-or-(CH 2) m-representative, wherein m is an integer 3,4,5 or 6; And n is an integer 1,2,3,4,5 or 6, and described method comprises carbamide compound shown in the formula IV and phosphorus pentahalides or the reaction of oxalyl halogen
Figure A0080523100052
Wherein n, Z and Z 1As mentioned above, and Z 2Be C 1-C 6Alkyl or benzyl, wherein said benzyl can be chosen wantonly on phenyl ring by 1-3 halogen, C 1-C 4Alkyl or C 1-C 4Haloalkyl replaces.
15. the method for claim 14, the two keys in its Chinese style IV compound mainly are (Z)-configuration.
16. the method for claim 14, wherein said phosphorus pentahalides are that phosphorus pentachloride and described oxalyl halogen are oxalyl chlorides.
17. the method for claim 14, wherein urea and phosphorus pentahalides or oxalyl halogen react in the presence of solvent.
18. the method for claim 17, wherein said solvent are selected from three oxyhalogen phosphorus, aromatic hydrocarbons, halogenated aryl hydrocarbon, carboxylic acid amide, aliphatic hydrocrbon and halogenated aliphatic hydrocarbon and composition thereof.
19. the method for claim 14, wherein urea and phosphorus pentahalides or oxalyl chloride react under about 0 ℃ of-100 ℃ of temperature.
20. the method for claim 19, wherein urea and phosphorus pentahalides or oxalyl chloride react under about 20 ℃ of-50 ℃ of temperature.
21. the method for claim 14, wherein Z and Z 1Be C independently respectively 1-C 6Alkyl; Z 2Be C 1-C 4Alkyl; With n be 1.
22. the method for claim 21, wherein Z and Z 1Identical, and represent methylidene or ethyl; And Z 2Be methyl or ethyl; With n be 1.
23. carbamide compound shown in the formula IV
Figure A0080523100061
Wherein Z and Z 1Be C independently respectively 1-C 8Alkyl, perhaps Z and Z 1Form 4-7 unit ring, wherein ZZ with the atom that they connected 1By-(CH 2) 2O (CH 2) 2-or-(CH 2) m-representative, wherein m is an integer 3,4,5 or 6; N is an integer 1,2,3,4,5 or 6; And Z 2Be C 1-C 6Alkyl or benzyl, wherein said benzyl can be chosen wantonly on phenyl ring by 1-3 halogen, C 1-C 4Alkyl or C 1-C 4Haloalkyl replaces.
24. the compound of claim 23, wherein said pair of key mainly is (Z)-configuration.
25. the compound of claim 23, wherein Z and Z 1Be C independently respectively 1-C 6Alkyl; Z 2Be C 1-C 4Alkyl; With n be 1.
26. the compound of claim 25, wherein Z and Z 1Identical, and represent methylidene or ethyl; And Z 2Be methyl or ethyl.
27. the compound of claim 23, wherein said compound is selected from 3-[(N, the N-formyl-dimethylamino) amino]-4,4, the 4-trifluoroacetic ethyl crotonate, (Z)-; 3-[(N, the N-formyl-dimethylamino) amino]-4,4,4-trifluoro methyl crotonate, (Z)-; 3-[(N, N-diethylamino formyl radical) amino]-4,4, the 4-trifluoroacetic ethyl crotonate, (Z)-; 3-[(N, N-diethylamino formyl radical) amino]-4,4,4-trifluoro methyl crotonate, (Z)-; 3-[(N-tetramethyleneimine carbonyl) amino]-4,4, the 4-trifluoroacetic ethyl crotonate, (Z)-; With 3-[(N-tetramethyleneimine carbonyl) amino]-4,4,4-trifluoro methyl crotonate, (Z)-.
28. the method for 6-shown in the preparation formula V (perfluoroalkyl) uracil compound Wherein n is an integer 1,2,3,4,5 or 6; Z 3Be hydrogen or C 1-C 6Alkyl; With Q be C 1-C 6Alkyl or optional phenyl, benzyl, heteroaryl or the methylene radical heteroaryl that replaces, described method comprises: (a) with carbamide compound shown in the formula IV
Figure A0080523100082
Wherein Z and Z 1Be C independently respectively 1-C 8Alkyl, perhaps Z and Z 1Form 4-7 unit ring, wherein ZZ with the atom that they connected 1By-(CH 2) 2O (CH 2) 2-or-(CH 2) m-representative, wherein m is an integer 3,4,5 or 6; Z 2Be C 1-C 6Alkyl or benzyl, wherein said benzyl can be chosen wantonly on phenyl ring by 1-3 halogen, C 1-C 4Alkyl or C 1-C 4Haloalkyl replaces; And n as mentioned above, with phosphorus pentahalides or the reaction of oxalyl halogen, to form 2-shown in the formula I (N, N-two replaces) amino-4-(perfluoroalkyl)-1,3-oxazine-6-ketone (b) with 2-(N, N-two replaces) amino-4-(perfluoroalkyl)-1, amine compound reacts in the presence of acid or alkali shown in 3-oxazine-6-ketone and the formula VI
QNH 2
(VI) wherein Q is as mentioned above to form 6-shown in the formula V (perfluoroalkyl) uracil compound, and wherein Z3 is a hydrogen; (c) optional wherein Z3 is the formula V alkylation of hydrogen.
29. the method for claim 28, the two keys in its Chinese style IV compound mainly are (Z)-configuration.
30. the method for claim 28, wherein said phosphorus pentahalides are that phosphorus pentachloride and described oxalyl halogen are oxalyl chlorides.
31. the method for claim 28, wherein said acid is selected from organic acid and mineral acid.
32. the method for claim 31, wherein said organic acid is C 1-C 6Paraffinic acid and described mineral acid are selected from hydrochloric acid, sulfuric acid and phosphoric acid.
33. the method for claim 31, wherein said acid is acetate.
34. the method for claim 28, wherein said alkali is selected from three (C 1-C 6Alkyl) amine, heterocycle tertiary amine and basic metal C 1-C 6Alkoxide.
35. the method for claim 34, wherein said alkali is selected from 1,8-diazabicylo [5.4.0] 11-7-alkene and 1,5-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-5-alkene.
36. the method for claim 28 is wherein chosen wantonly in the presence of first kind of solvent, with urea and phosphorus pentahalides or the reaction of oxalyl halogen, and in the presence of second kind of solvent, with 2-(N, N-two replaces) amino-4-(perfluoroalkyl)-1,3-oxazine-6-ketone and amine and acid-respons.
37. the method for claim 36, wherein said solvent is selected from three oxyhalogen phosphorus, aromatic hydrocarbons, halogenated aryl hydrocarbon, carboxylic acid amide, aliphatic hydrocrbon and halogenated aliphatic hydrocarbon and composition thereof, and described second kind of solvent is selected from carboxylic acid amide, dialkyl sulphoxide, aromatic hydrocarbons, halogenated aryl hydrocarbon, aliphatic hydrocrbon, halogenated aliphatic hydrocarbon, paraffinic acid, ketone, ether, nitrile and water and composition thereof.
38. the method for claim 28 is wherein reacted urea and phosphorus pentahalides or oxalyl chloride under about 0 ℃ of-100 ℃ of temperature, and with 2-(N, N-two replaces) amino-4-(perfluoroalkyl)-1,3-oxazine-6-ketone and amine and sourly react under about 20 ℃ of-150 ℃ of temperature.
39. the method for claim 28, wherein step (c) comprises with Z3 wherein it being that the formula V compound of hydrogen and formula VII alkylogen or formula VIII sulfuric acid dialkyl react in the presence of alkali
XZ 3Or
Figure A0080523100101
(VII) wherein X is chlorine, bromine or iodine, and Z 3Be C 1-C 6Alkyl.
40. the method for claim 28, wherein n is 1; Z 3Be hydrogen or C 1-C 4Alkyl; Q is
Figure A0080523100111
G is CH 2Or chemical bond; G 1Be CX 5Or N; G 2Be CX 4Or N; X 1Be hydrogen, halogen or the optional C that is replaced by an epoxy group(ing) 1-C 6Alkyl, X 2Be hydrogen, halogen, NRR 1, CO 2R 2, C (O) R 3, OR 4, SO 2R 5, SO 2NR 6R 7,
C(R 8)(OR 9) 2、C(R 10)＝NOR 11、C(R 12)＝C(R 13)-C(OR 14)＝NOR 15、
CH 2O-NCO 2R 16、
Optional by a C 1-C 6Alkoxyl group or one or two C 1-C 41 of alkyl replacement, the 3-dioxy
The heterocycle pentane,
Optional by a C 1-C 6Alkoxyl group or one or two C 1-C 41 of alkyl replacement, the 3-dioxy
Heterocyclic pentene ketone,
Optional by a CO2R 2Group and the C that halogen atom replaces1-C 4Alkyl, and X3Hydrogen, halogen, C1-C 4Haloalkyl, CO2R 17, cyano group, C1-C 4Halogenated alkoxy, OR18Or C1-C 4Alkyl, perhaps work as X1And X2While with their connected atoms, connecting together, they can form 5 yuan or 6 rings, wherein X1X 2Or X2X 1By following representative :-OC (R20)(R 21)O-、-CH 2S(O) pN(R 22)-、-SC(R 23)＝N-、 -CH＝CH-CH(R 11)O-、-OC(O)N-、-SC(R 24)＝N-、-ON(R 25)C(O)-、 -OC(CO 2R 26)＝C(R 27)-、-NC(R 28)＝C(SR 29)-、-CH＝C(CO 2R 30)O-、 -CH 2CH(R 31) O-or-OC (R32)(R 33) C (O)-, perhaps work as X2And X3While with their connected atoms, connecting together, they can form 5 yuan or 6 rings, wherein X2X 3Or X3X 2By following representative :-NC (R34)＝NC(S)-、-N(R 35)N＝C(R 36)-、-N(R 37)C(R 38)＝N-、 -N(R 38)C(O)CH 2O-、-N(R 39)C(O)CH＝CH-、-S-N＝C(R 40)-、 -O-N＝C(R 41)-、-N＝N-N(R 42)-、-C(R 43)(R 44)C(O)N(R 45)-or-N (R46)C(O)C(R 47)(R 48)-； X 4Hydrogen, halogen or OR19； X 5It is hydrogen or halogen; R, R56、R 64、R 69、R 70、R 77And R91Be hydrogen, SO independently respectively2R 49、C 1-C 4Alkyl, C3-C 7Cycloalkyl, C3-C 6Alkenyl, C3-C 6Alkynyl group, phenyl or benzyl; R1Hydrogen, SO2R 50、C(O)R 51, amino or optional by CO2R 52Or C (O) R63The C that replaces1-C 4Alkyl; R2、R 16、R 17、R 26、R 30、R 68、R 75、R 76、R 82And R88Be hydrogen, C independently respectively1-C 8Haloalkyl, C3-C 8Alkenyl, C3-C 6Alkynyl group, phenyl, benzyl, furfuryl, pyridine radicals, thienyl, C1-C 8Alkyl, described group is optional by CO2R 54, morpholine or C (O) R55Replace, or alkali metal, alkaline-earth metal, ammonium or organic ammonium cation; R3、R 66、R 67、R 81、R 85And R89Be hydrogen, C independently respectively1-C 6Alkyl, C3-C 6Alkenyl, C3-C 6Alkynyl group, NR56R 57, phenyl or benzyl; R4、R 18、R 19And R65Be hydrogen, C independently respectively1-C 6Alkyl, C3-C 6Alkenyl, C3-C 6Alkynyl group, C1-C 4Haloalkyl, C (O) R58、C(S)R 59Or benzyl; R5And R72Be C independently respectively1-C 6Alkyl, C1-C 6Haloalkyl, NR60R 61, imidazoles or indazole; R6、R 11、R 12、R 14、R 15、R 20、R 21、R 22、R 25、R 28、R 29、R 31、R 32、R 33、 R 35、R 45、R 46、R 63And R80Be hydrogen or C independently respectively1-C 4Alkyl; R7Hydrogen, C3-C 6Alkenyl, C3-C 6Alkynyl group, benzyl or C1-C 4Alkyl, described group can be chosen wantonly by cyano group or C (O) R62Replace; R8And R27Be hydrogen, C independently respectively1-C 4Alkyl or C1-C 4Alkoxyl; R9And R90Be C independently respectively1-C 6Alkyl; R10Hydrogen, C1-C 6Alkyl, phenyl or benzyl; R13、R 24And R36Be hydrogen, C independently respectively1-C 6Alkyl or halogen; R23Hydrogen or NR63R 64； R 34Hydrogen, C1-C 4Alkyl or C1-C 4Haloalkyl; R37Hydrogen, C1-C 4Alkyl or C2-C 8The alkoxyl alkyl; R38And R39Be hydrogen, C independently respectively1-C 4Alkyl, C1-C 4Haloalkyl, C3-C 6Alkenyl or C3-C 6Alkynyl group; R40、R 41And R42Be hydrogen, halogen, cyano group, OR independently respectively65、C(O)R 66、C(S)R 67、 CO 2R 68、C(＝NOR 69)、C 1-C 8Alkyl, C3-C 7Cycloalkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group, wherein each group can be chosen arbitrarily combined following group wantonly and replaces: 1-6 halogen atom, a 1-3 C1-C 10Alkoxyl, 1 or 2 C1-C 6Halogenated alkoxy, 1 or 2 NR70R 71, 1 or 2 S (O)qR 72, 1 or 2 cyano group, 1 or 2 C3-C 7Cycloalkyl, an OSO2R 73, 1 or 2 C (O) R74, 1 or 2 CO2R 75, 1 or 2 C (O) SR76, 1 or 2 C (O) NR77R 78, a 1-3 OR79, 1 or 2 P (O) (OR80) 2, one optional by 1-3 C1-C 4Alkyl replace 1, the 3-dioxolane or one optional by 1-3 C1-C 4Alkyl replace 1, the 3-dioxane, perhaps phenyl or benzyl, the optional arbitrarily combined following group of described phenyl or benzyl replaces: 1-3 halogen atom, a 1-3 C1-C 6Alkyl, a 1-3 C1-C 8Alkoxyl, a C3-C 7Cycloalkyl, a C1-C 4Haloalkyl, a C1-C 4Alkylthio group, cyano group, nitro, a C (O) R81, a CO2R 82, an OR83, a SR84, a C1-C 6Alkoxyl methyl, a methylol, a C3-C 8Alkenyloxy methyl or a C1-C 8The halogenated alkoxy methyl; R43、R 44、R 47And R48Be hydrogen, C independently respectively1-C 4Alkyl, C1-C 4Haloalkyl, C3-C 6Alkenyl, C3-C 6Alkynyl group or C3-C 7Cycloalkyl, perhaps R43And R44Or R47And R48Form C together with atom that they connect3-C 7Cycloalkyl; R49、R 50And R86Be C independently respectively1-C 6Alkyl, NR93R 94、C 1-C 4Haloalkyl, C3-C 6Alkenyl, C3-C 6Alkynyl group or benzyl; R51、R 52、R 53、R 54、R 55、R 57、R 58、R 59、R 60、R 61、R 62、R 71、R 73、R 74、 R 78、R 87And R92Be hydrogen, C independently respectively1-C 6Alkyl, C3-C 7Cycloalkyl, C1-C 6Haloalkyl, C3-C 6Alkenyl, C3-C 6Alkynyl group, phenyl or benzyl; R79、R 83And R84Be hydrogen, C (O) R independently respectively85、SO 2R 86、C 1-C 6Haloalkyl, C2-C 6Alkenyl, C5-C 8Cycloalkenyl group, C2-C 6Alkynyl group, phenyl, benzyl or C1-C 10Alkyl, described group is optional to be replaced by following group: hydroxyl, benzyloxy, OC (O) R87、C 1-C 6Alkoxyl, CO2R 88、C(O)R 89、C(OR 90) 2、C(O)NR 91R 92Or cyano group; R93And R94Be hydrogen, C independently respectively1-C 4Haloalkyl, C2-C 6Alkenyl, C3-C 8Cycloalkyl, C1-C 8Alkyl, described group is optional by 1 or 2 C1-C 4Alkoxyl or cyano group alkyl replace, perhaps benzyl or phenyl, and the optional arbitrarily combined following group of described phenyl or benzyl replaces: 1-3 halogen atom, a 1-3 C1-C 4Alkyl, a 1-3 C1-C 4Haloalkyl, a 1-3 C1-C 4Alkoxyl, a 1-3 C1-C 4Halogenated alkoxy, a cyano group or a nitro, and work as R93And R94When the atom that is connected with them connects together, the two ring heterocycles that they can form 5-12 unit's monocycle or condense, described ring can be chosen wantonly by one or more halogen, cyano group, nitro, amino, hydroxyl, C of being independently selected from1-C 4Alkyl, C1-C 4Haloalkyl, C1-C 4Alkoxyl, C1-C 4Halogenated alkoxy and C1-C 4The group of halogenated alkyl sulfonyl replaces; P and q are respectively 0,1 or 2 independently; Z and Z are C respectively independently1-C 6Alkyl; And Z2C1-C 4Alkyl.
41. the method for claim 40, wherein Z3Hydrogen or methyl; X1Hydrogen, fluorine or the optional C that is replaced by an epoxy radicals1-C 3Alkyl, X2Hydrogen, halogen, NRR1、CO 2R 2、C(O)R 3、OR 4、SO 2R 5、SO 2NR 6R 7、 C(R 8)(OR 9) 2、C(R 10)＝NOR 11、 C(R 12)＝C(R 13)-C(OR 14)＝NOR 15、CH 2O-NCO 2R 16, optional by a C1-C 6Alkoxyl or one or two C1-C 41 of alkyl replacement, 3-dioxolane, optional by a C1-C 6Alkoxyl or one or two C1-C 41 of alkyl replacement, 3-dioxolone, optional by a CO2R 2Group and the C that halogen atom replaces1-C 4Alkyl, and X3Hydrogen, halogen, C1-C 4Haloalkyl, CO2R 17, cyano group, C1-C 4Halogenated alkoxy, OR18Or C1-C 4Alkyl, perhaps work as X1And X2While with their connected atoms, connecting together, they can form 5 yuan or 6 rings, wherein X1X 2Or X2X 1By following representative :-OC (R20)(R 21)O-、-CH 2S(O) pN(R 22)-、-SC(R 23)＝N-、 -CH＝CH-CH(R 11)O-、-OC(O)N-、-SC(R 24)＝N-、-ON(R 25)C(O)-、 -OC(CO 2R 26)＝CH-、-NC(R 28)＝C(SR 29)-、-CH＝C(CO 2R 30)O-、 -CH 2CH(R 31) O-or-OC (R32)(R 33) C (O)-, perhaps work as X2And X3While with their connected atoms, connecting together, they can form 5 yuan or 6 rings, wherein X2X 3Or X3X 2By following representative :-NC (R34)＝NC(S)-、-N(R 35)N＝C(R 36)-、-N(R 37)C(R 38)＝N-、 -N(R 38)C(O)CH 2O-、-N(R 39)C(O)CH＝CH-、-S-N＝C(R 40)-、 -O-N＝C(R 41)-、-N＝N-N(R 42)-、-C(R 43)(R 44)C(O)N(R 45)-or-N (R46)C(O)C(R 47)(R 48)-； X 4Hydrogen, halogen or OR19； X 5It is hydrogen or halogen; R, R64、R 69And R77Be hydrogen, SO independently respectively2R 49Or C1-C 4Alkyl; R1Hydrogen, SO2R 50、C(O)R 51, amino or optional by CO2R 52Or C (O) R53The C that replaces1-C 4Alkyl; R2、R 16、R 17、R 26、R 30、R 68、R 75、R 76、R 82And R88Be hydrogen, C independently respectively3-C 6Alkenyl or C1-C 4Alkyl, described group is optional by CO2R 54, morpholine or C (O) R55Replace; R3、R 66、R 67、R 85And R89Be hydrogen, C independently respectively1-C 4Alkyl or NR56R 57； R 4、R 18And R19Be hydrogen, C independently respectively1-C 4Alkyl, C1-C 4Haloalkyl, C (O) R58、 C 3-C 4Alkenyl or C3-C 4Alkynyl group; R56SO2R 49； R 57Hydrogen or C1-C 4Alkyl; R5And R72Be NR independently respectively60R 61Or indazole; R6、R 11、R 12、R 14、R 15、R 20、R 21、R 22、R 25、R 28、R 29、R 31、R 32、R 33、 R 35、R 45、R 46And R80Be hydrogen or methyl independently respectively; R7Optional by cyano group or C (O) R62The C that replaces1-C 4Alkyl; R8Hydrogen or C1-C 4Alkoxyl; R9And R90Be C independently respectively1-C 4Alkyl; R10Hydrogen or C1-C 3Alkyl; R13、R 24And R36Be hydrogen or chlorine independently respectively; R23NR63R 64； R 34C1-C 3Haloalkyl; R37C2-C 4The alkoxyl alkyl; R38And R39Be C independently respectively1-C 3Haloalkyl, C1-C 3Alkyl or propargyl; R40、R 41And R42Be hydrogen, C (O) R independently respectively66、C(S)R 67、CO 2R 68、C(＝NOR 69), the C that replaces of optional arbitrarily combined following group1-C 3Alkyl: 1 or 2 halogen atom, 1 or 2 C1-C 3Alkoxyl, 1 or 2 C1-C 3Halogenated alkoxy, a SO2R 72, 1 or 2 cyano group, a C3-C 5Cycloalkyl, an OSO2R 73, C (O) R74, a CO2R 75, C (O) SR76, C (O) NR77R 78, a 1-2 OR79, P (O) (OR80) 2, one 1,3-dioxolane group or one 1,3-dioxane group, perhaps phenyl, the optional arbitrarily combined following group of described phenyl replaces: a halogen atom, 1 or 2 methyl, a methoxyl group, a halo methyl or an OR83； R 43、R 44、R 47And R48Be hydrogen or methyl, perhaps R independently respectively43And R44Or R47And R48Form cyclopropyl together with atom that they connect; R49、R 50And R86Be C independently respectively1-C 4Alkyl or NR93R 94； R 51、R 52、R 53、R 54、R 55、R 58、R 60、R 61、R 62、R 73、R 74、R 78And R87Be hydrogen, C independently respectively1-C 4Alkyl or C1-C 4Haloalkyl; R79And R83Be hydrogen, C (O) R independently respectively85、SO 2R 86、C 1-C 4Haloalkyl, C3-C 4Alkenyl or C1-C 3Alkyl, described group is optional to be replaced by following group: an OC (O) R87、 CO 2R 88、C(O)R 89、C(OR 90) 2Or cyano group; R93And R94Be hydrogen or C independently respectively1-C 8Alkyl; P is 0,1 or 2; Z and Z1Identical, and represent methylidene or ethyl; And Z2Methyl or ethyl.
42. be used for the method for the claim 28 of 6-shown in the preparation formula IX (trifluoromethyl) uracil compound,
Figure A0080523100171
Z wherein 3Be hydrogen or methyl; X 5It is hydrogen or halogen; R 40Be hydrogen, C (O) R 66, C (S) R 67, CO 2R 68, the C that replaces of optional arbitrarily combined following radicals 1-C 3Alkyl: 1 or 2 halogen atom, 1 or 2 C 1-C 3Alkoxyl group, 1 or 2 C 1-C 3Halogenated alkoxy, a SO 2R 72, 1 or 2 cyano group, a C 3-C 5Cycloalkyl, an OSO 2R 73, 1 or 2 OR 79, P (O) (OR 80) 2, one 1,3-dioxolane group or one 1,3-dioxane group, perhaps phenyl, the optional arbitrarily combined following radicals of described phenyl replaces: a halogen atom, 1 or 2 methyl, a methoxyl group, a halogenated methyl or an OR 83R 66, R 67, R 85And R 89Be hydrogen, C independently respectively 1-C 4Alkyl or NR 56R 57R 56Be SO 2R 49R 57Be hydrogen or C 1-C 4Alkyl; R 49And R 86Be C independently respectively 1-C 4Alkyl or NR 93R 94R 93And R 94Be hydrogen or C independently respectively 1-C 8Alkyl; R 68And R 88Be hydrogen, C independently respectively 3-C 6Alkenyl or C 1-C 4Alkyl, described group is optional by CO 2R 54, morpholine or C (O) R 55Replace; R 54, R 55, R 60, R 61, R 73And R 87Be hydrogen, C independently respectively 1-C 4Alkyl or C 1-C 4Haloalkyl; R 72Be NR 60R 61Or indazole; R 79And R 83Be hydrogen, C (O) R independently respectively 85, SO 2R 86, C 1-C 4Haloalkyl, C 3-C 4Alkenyl or C 1-C 3Alkyl, described group is optional to be replaced by following radicals: an OC (O) R 87, CO 2R 88, C (O) R 89, C (OR 90) 2Or cyano group; R 80Be hydrogen or methyl; And R 90Be C 1-C 4Alkyl.
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