EP1171427A1 - Fabrication de composes 6-(perfluoroalkyl) uracil a partir de composes d'uree - Google Patents

Fabrication de composes 6-(perfluoroalkyl) uracil a partir de composes d'uree

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Publication number
EP1171427A1
EP1171427A1 EP00910177A EP00910177A EP1171427A1 EP 1171427 A1 EP1171427 A1 EP 1171427A1 EP 00910177 A EP00910177 A EP 00910177A EP 00910177 A EP00910177 A EP 00910177A EP 1171427 A1 EP1171427 A1 EP 1171427A1
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European Patent Office
Prior art keywords
group
alkyl
hydrogen
groups
optionally substituted
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EP00910177A
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German (de)
English (en)
Inventor
Venkataraman Kameswaran
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BASF SE
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American Cyanamid Co
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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
    • 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

Definitions

  • 6- (Perfluoroalkyl) uracil compounds are useful as herbicidal agents and methods for their preparation are known in the art.
  • 6- (Perfluoroalkyl) uracil compounds may be prepared by reacting 2- (N,N-disubstituted) amino-4- (perfluoroalkyl) -1, 3-oxazin-6-one compounds with amine compounds.
  • an object of the present invention to provide an improved process for the preparation of 6- (perfluoroalkyl) uracil compounds which avoids the use of 2- (N,N-disubstituted) amino-4- (perfluoroalkyl) -1,3-oxazin- 6-one compounds .
  • the present invention provides a new process for the preparation of 6- (perfluoroalkyl) uracil compounds having the structural formula I
  • n is an integer of 1, 2, 3, 4, 5 or 6 ;
  • Y is hydrogen or C j -Cgalkyl; and
  • Q is a C 1 -C 6 alkyl group or an optionally substituted phenyl, benzyl, heteroaryl or methyleneheteroaryl group , which process comprises :
  • Z and Z are each independently C ⁇ -C ⁇ alky! or Z and Z x may be taken together with the atom to which they are attached to form a 4- to 7-membered ring wherein ZZi is represented by - (CH 2 ) 2 0 (CH 2 ) 2 - or -(CH 2 ) m - where m is an integer of 3 , 4, 5 or 6; Z 2 is Ci-Cgalkyl or benzyl optionally substituted on the phenyl ring with any combination of from one to three halogen, C ⁇ -Calkyl or C 1 -C 4 haloalkyl groups; and n is as described above, with an amine compound having the structural formula III
  • the 6- (perfluoroalkyl) uracil compounds of formula I wherein Y is hydrogen are prepared by reacting a urea compound of formula II with an amine compound of formula III and an acid or base, preferably at a temperature ranging from about 20°C to 150°C, in the presence of a solvent .
  • the double bond in the formula II compounds is predominately in the (Z) - configuration.
  • the present invention provides an improved process for the preparation of 6- (perfluoro- alkyDuracil compounds which avoids the use of 2-(N,N- disubstituted) amino-4- (perfluoroalkyl) -l,3-oxazin-6-one compounds .
  • the product formula I compounds may be isolated using conventional isolation procedures such as diluting the reaction mixture with water and separating the product or extracting the product with a suitable extraction solvent.
  • conventional extraction solvents such as diethyl ether, ethyl acetate, toluene, methylene chloride, and the like, and mixtures thereof may be utilized.
  • Acids suitable for use in this invention include organic acids including, but not limited to, C 1 -C 6 alkanoic acids such as formic acid, acetic acid, propionic acid and the like; and mineral acids including, but not limited to, hydrochloric acid, sulfuric acid, phosphoric acid and the like.
  • a preferred acid is acetic acid.
  • Bases suitable for use in the process of the present invention include, but are not limited to, tri(C 1 -C 6 . alkyl) amines such as tri ethylamine, triethyla ine, tripropylamine, tributylamine, diisopropylethylamine and the like; heterocyclic tertiary amines such as 1,8-diaza- bicyclo [5.4.0] undec-7-ene (DBU) , 1, 5-diazabicyclo- [4.3.0]non-5-ene (DBN) , 1, 4-diazabicyclo [2.2.2] octane, pyridine, substituted pyridines, quinoline, substituted quinolines and the like,- and alkali metal C 1 -C 6 alkoxides such as potassium tert-butoxide, sodium tert-butoxide and the like.
  • tri(C 1 -C 6 . alkyl) amines such as tri e
  • Preferred bases include 1, 8-diazabicyclo- [5.4.0]undec-7-ene and 1, 5-diazabicyclo [4.3.0] non-5-ene .
  • Solvents suitable for use in step (a) of the process of this invention include, but are not limited to, carboxylic acid amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; dialkyl sulfoxides such as dimethyl sulfoxide and the like; aromatic hydrocarbons such as toluene, benzene, xylenes, mesitylene and the like; halogenated aromatic hydro- carbons such as chlorobenzene, fluorobenzene and the like; aliphatic hydrocarbons such as pentane, hexane, heptane and the like; halogenated aliphatic hydrocarbons such as methylene chloride, chloroform, carbon tetra- chloride, 1, 2-dichloroethan
  • step (b) alkylation procedure comprises reacting the formula I compound wherein Y is hydrogen with an alkyl halide having the structural formula IV or a dialkylsulfate ester having the structural formula V
  • X is chlorine, bromine or iodine, and Y is in the presence of a base.
  • Bases suitable for use in the alkylation procedures of this invention include conventional bases known in the art including, but not limited to, alkali metal hydrides such as sodium hydride and the like; alkali metal C j ⁇ -C 8 alkoxides such as potassium tert-butoxide, sodium tert-butoxide and the like; alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkaline earth metal hydroxides such as calcium hydroxide and the like; and alkaline earth metal carbonates such as calcium carbonate and the like.
  • alkali metal hydrides such as sodium hydride and the like
  • alkali metal C j ⁇ -C 8 alkoxides such as potassium tert-butoxide, sodium tert-butoxide and the like
  • alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and the like
  • alkali metal carbonates such as sodium
  • Preferred formula II compounds for use in the process of this invention are those wherein
  • Z and Z x are each independently C- L -Cgal yl
  • Z 2 is C 1 -C 4 alkyl; and n is i.
  • More preferred urea compounds of formula II for use in the process of the present invention are those wherein
  • Z and Z ;L are the same and represent methyl or ethyl ;
  • Z 2 is methyl or ethyl; and n is 1.
  • Preferred formula I compounds which may be prepared by the process of the present invention are those wherein n is 1;
  • Y is hydrogen or C 1 -C 4 alkyl
  • X 4 is hydrogen, halogen or 0R 19 ;
  • X 5 is hydrogen or halogen;
  • R, R S6 , R 64 , R 69 , R 70 , R 77 and R 91 are each independently hydrogen, S0 2 R 49 , C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 3 -Cgalkenyl, C 3 -C 6 alkynyl , phenyl or benzyl;
  • R x is hydrogen, SO 2 R 50 , C(0)R 51 , amino or C 1 -C 4 alkyl optionally substituted with C0 2 R 52 or C(0)R 53 ;
  • C 1 -C 8 alkyl optionally substituted with C0 2 R 54 , morpholine or C(0)R ss , or an alkali metal, an alkaline earth metal, ammonium or organic ammonium cation ;
  • R 3 , R 66 , R 67 , R 81 , R 8S and R 89 are each independently hydrogen , C ⁇ C g alkyl, C 3 -C ⁇ alkenyl, C 3 -Cgalkynyl, NR S gR 57 , phenyl or benzyl ;
  • R 4 , R 18 , R 19 and R 65 are each independently hydrogen,
  • R 5 and R 72 are each independently Ci-Cgalkyl, C - Cghaloalkyl,
  • R 35 , R 45 , R 46 , R 63 and R 80 are each independently hydrogen or C 1 -C 4 alkyl
  • R 7 is hydrogen, C 3 -C 6 alkenyl , C 3 -C 6 alkynyl , benzyl, or C 1 -C 4 alkyl optionally substituted with cyano or C(0)R 62 ;
  • R 8 and R 27 are each independently hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy;
  • R 9 and R 90 are each independently R 10 is hydrogen, phenyl or benzyl; R 13 , R 24 and R 36 are each independently hydrogen, or halogen; R 23 is hydrogen or ⁇ R ⁇ 3 R 64 ;
  • R 34 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl
  • R 37 is hydrogen, C 1 -C 4 alkyl or C 2 -C 8 alkoxyalkyl
  • R 38 and R 3g are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 alkenyl or C 3 -C 6 alkynyl
  • R 43 / R 44 , R 47 and R 48 are each independently hydrogen,
  • R 49 , R 50 and R 86 are each independently C ⁇ C g alkyl, NR 93 R 94 , C 1 -C 4 haloakyl, C 3 -C ⁇ alkenyl, C 3 -C 6 alkynyl or benzyl; R S1 , R 52 , R 53 , R S4 , R 55 , R S7 , R 5g , R 59 , R €Q , R 61 , R ⁇ 2 , R 71 , R 73 , R 74 , R 78 , R 87 and R 92
  • R 93 and R 94 are each independently hydrogen, C 1 -C 4 haloalkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkyl optionally substituted with one or two
  • C 1 -C 4 alkoxy groups or one cyanoalkyl group or benzyl or phenyl optionally substituted with any combination of one to three halogen atoms, one to three C 1 -C 4 alkyl groups, one to three C 1 -C 4 haloalkyl groups, one to three C 1 -C 4 alkoxy groups, one to three C ⁇ - j haloalkoxy groups, one cyano group or one nitro group, and when R 93 and R 94 are taken together with the atom to which they are attached, they form a 5- to 12- membered monocyclic or fused bicyclic, heterocyclic ring optionally substituted with one or more groups independently selected from halogen, cyano, nitro, amino, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl,
  • herbicidal agents which may be prepared by the process of this invention are those wherein n is 1; Y is hydrogen or methyl;
  • G is CH 2 or a bond;
  • G x is CX 5 or N;
  • G 2 is CX 4 or N;
  • X x is hydrogen, fluorine or optionally substituted with one epoxy group
  • X 3 is hydrogen, halogen, C 1 -C 4 haloalkyl, C0 2 R 17 , cyano, C 1 -C 4 haloalkoxy, OR 18 or C 1 -C 4 alkyl, or when X x and X 2 are taken together with the atoms to which they are attached, they may form a five- or six- membered ring wherein X j X- or X 2 X X is represented by: -OC(R 20 ) (R 21 )0-, -CH 2 S(0) p N(R 22 )
  • X 4 is hydrogen, halogen or OR 19 ;
  • X 5 is hydrogen or halogen;
  • R, R 64 , R 69 and R 77 are each independently hydrogen
  • R x is hydrogen, SO 2 R 50 , C(0)R 51 , amino or C 1 -C 4 alkyl optionally substituted with C0 2 R s2 or C(0)R 53 ;
  • R 2 , Ris, R 17 / K- 26 ' ⁇ 30 ⁇ 6 ⁇ ' ⁇ 75 ⁇ 76 ⁇ 82 an R 88 are each independently hydrogen, C 3 -C 6 alkenyl or C 1 -C 4 alkyl optionally substituted with C0 2 R 54 , morpholine or C(0)R 55 ;
  • R 3 , R 6S , R 67 , R 85 and R 89 are each independently hydrogen, C 1 -C 4 alkyl or NR 56 R S7 ;
  • R 4 , R 18 and R 19 are each independently hydrogen
  • R 5 and R 72 are each independently NR 50 R 61 or indazole;
  • R 35 R 45 R 46 an d R 8 o are each independently hydrogen or methyl ;
  • R 7 is C 1 -C 4 alkyl optionally substituted with cyano or C(0)R 62 ;
  • R 8 is hydrogen or C 1 -C 4 alkoxy;
  • R 9 and R 90 are each independently C 1 -C 4 alkyl;
  • R 10 is hydrogen or C 1 -C 3 alkyl;
  • R 13 , R 24 and R 36 are each independently hydrogen or chlorine ;
  • R 23 is ⁇ R 63 R 64 ;
  • R 34 is C ⁇ -C ⁇ haloalkyl;
  • R 37 is C 2 -C 4 alkoxyalkyl;
  • R 38 and R 39 are each independently C 1 -C 3 haloalkyl , C ⁇ C j alkyl or propargyl;
  • C 1 -C 3 alkyl optionally substituted with any combi- nation of one or two halogen atoms, one or two
  • 0R 79 groups one P(O) (OR 80 ) 2 group, one 1,3- dioxolane group or one 1,3 -dioxane group, or phenyl optionally substituted with any combination of one halogen atom, one or two methyl groups, one methoxy group, one halomethyl group or one
  • R 43/ R 44/ R 47 nd R 48 are each independently hydrogen or methyl, or R 43 and R 44 or R 47 and R 48 may be taken together with the atom to which they are attached to form a cyclopropyl group;
  • R 49 , R so and R 86 are each independently C 1 -C 4 alkyl or NR 93 R 94 ; are each independently hydrogen, C 1 -C 4 alkyl or alkyl ;
  • R 79 and R 83 are each independently hydrogen, C (0) R 8S , S0 2 R 86 , C 1 -C 4 haloalkyl , C 3 -C 4 alkenyl or C 1 -C 3 alkyl substituted with one OC (0) R 87 ,
  • R 93 and R 94 are each independently hydrogen or C ⁇ C g alkyl ; and p is 0 , 1 or 2 .
  • the process of the present invention is especially useful for the preparation of 6 - (trifluoromethyl ) uracil compounds having the structural formula VI
  • Y is hydrogen or methyl
  • X 5 is hydrogen or halogen
  • R 40 is hydrogen, C(0)R 66 , C(S)R 67 , C0 2 R 68 ,
  • C 1 -C 3 alkyl optionally substituted with any combination of one or two halogen atoms, one or two C 1 -C 3 alkoxy groups, one or two C 1 -C 3 haloalkoxy groups, one S0 2 R 72 group, one or two cyano groups, one C 3 -C 5 cycloalkyl group, one 0S0 2 R 73 group, one or two 0R 79 groups, one P(O) (OR 80 ) 2 group, one 1, 3-dioxolane group or one 1,3 -dioxane group, or phenyl optionally substituted with any combination of one halogen atom, one or two methyl groups, one methoxy group, one halomethyl group or one
  • R R c R 85 and R 89 are each independently hydrogen ,
  • R S7 is hydrogen or C 1 -C 4 alkyl
  • R 4 and R 8S are each independently C 1 -C 4 alkyl or NR 93 R 94
  • R 9 and R 94 are each independently hydrogen or Ci-C 8 al yl
  • R_ and R 88 are each independently hydrogen, C 3 -C 6 alkenyl or C 1 -C 4 alkyl optionally substituted with C0 2 R 54 , morpholine or C(0)R 55
  • R 54 , R ss , R 60 , R 61 , R 73 and R 87 are each independently hydrogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl
  • R 72 is NRg 0 R 61 or indazole
  • R 79 and R 83 are each independently hydrogen C(0)R 85 , S0 2 R 86 , C 1 -C 4 haloalkyl, C 3 -C 4 alkenyl or
  • halogen hereinabove are fluorine, chlorine, bromine and iodine.
  • halomethyl “Ci-C.haloalkyl”, “C 1 -C 3 haloalkoxy”, “C 1 -C 4 haloalkoxy” and are defined as a methyl, C 1 -C 4 alkyl, C.,-C 8 alkyl, C 1 -C 3 alkoxy, C 1 -C 4 alkoxy or group substituted with one or more halogen atoms.
  • alkali metals include sodium, potassium and lithium
  • alkaline earth metals include calcium and magnesium.
  • Organic ammonium cations suitable for use in the present invention include, but are not limited to, a group consisting of a positively charged nitrogen atom joined to from one to four aliphatic groups, each containing from one to sixteen carbon atoms .
  • 5- to 12-membered monocyclic or fused bicyclic, heterocyclic rings include, but are not limited to, benzimidazole, imidazole, imidazoline-2- thione, indole, isatoic anhydride, morpholine, piperazine, piperidine, purine, pyrazole, pyrrole, pyrrolidine and 1, 2, 4-triazole rings wherein each ring is optionally substituted with one or more groups independently selected from halogen, cyano, nitro, amino, hydroxyl, C x -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, or C 1 -C 4
  • n and Z 2 are as described hereinabove with a base and a carbamoyl chloride compound having the structural formula VIII
  • Formula VII ⁇ -amino- ⁇ - (perfluoroalkyl) acrylate compounds are known in the art and may be prepared according to the procedures described in U.S. 5,777,154; Journal of Heterocyclic Chemistry, 9, pages 513-522
  • Carbamoyl chloride compounds of formula VIII are known in the art and may be prepared by conventional procedures. In addition, certain formula VIII carbamoyl chloride compounds are commercially available.
  • X 1# X s and R 40 are as described hereinabove, may be prepared, as shown in Flow Diagram I, by cyclizing a ketone of formula IX with sulfur and ammonium hydroxide or ammonia to form a nitrobenzisothiazole of formula X, and reducing the formula X compound using conventional reducing agents such as iron in acetic acid.
  • X x , X 5 and R 41 are as described hereinabove, may be prepared, as illustrated in Flow Diagram II, by reacting a ketone of formula XI with hydroxylamine hydrochloride optionally in the presence of sodium acetate to form an oxime of formula XII, cyclizing the formula XII compound with a base such as potassium hydroxide to form a nitrobenzisoxazole of formula XIII, and reducing the formula XIII compound using conventional reducing agents such as tin (II) chloride in acetic acid.
  • a base such as potassium hydroxide
  • formula XIII nitrobenzisoxazole compounds may be prepared, as shown in Flow Diagram III, by reacting a ketone of formula XIV with hydroxylamine hydrochloride optionally in the presence of a base such as sodium acetate to form an oxime of formula XV, cyclizing the formula XV compound with 1, 1 ' -carbonyl- diimidazole in the presence of a base such as tri- ethylamine to form a benzisoxazole of formula XVI, and nitrating the formula XVI compound using conventional methods such as a nitric acid/sulfuric acid mixture.
  • FLOW DIAGRAM III FLOW DIAGRAM III
  • Formula X and XIII intermediate compounds wherein R 40 and R 41 are Cl or Br may be prepared, as shown in Flow Diagram V, by reacting a 5-nitrobenzisoxazol-3-ol or 5- nitrobenzisothiazol-3-ol of formula XVIII with phosphorous oxychloride, phosphorous oxybromide or phosphorous pentabromide .
  • Ethyl 3-amino-4,4,4-trifluorocrotonate (18.4 g, 100 mmol) is added to a stirred solution of sodium hydride (60% in mineral oil, 9.6 g, 250 mmol) in N,N-dimethyl- formamide (60 mL) at 5°C under nitrogen over a 60 minute period.
  • the reaction mixture is allowed to warm to and held at room temperature for 15 minutes, cooled to 5°C, and treated with dimethylcarbamoylchloride (21.6g, 200 mmol) over a 60 minute period.
  • the resultant solution is then warmed to and held at room temperature for 2 hours, diluted with water (150 mL) , and extracted with ethyl acetate (2 x 150 mL) .
  • the combined organic layers are dried, filtered and concentrated, and the mineral oil layer is removed to obtain a residue.
  • a mixture of aluminum chloride (33.3 g, 25.0 mmol) in methylene chloride is cooled to about 5 °C, treated over one hour with p-methylanisole (31.6 g, 25.0 mmol) while maintaining the reaction mixture temperature below 10 °C, treated over 20 minutes with a solution of 2-chloro-5-nitrobenzoyl chloride (50.0 g, 22.7 mmol) in methylene chloride while maintaining the reaction mixture temperature below 10 °C, warmed to and stirred at room temperature for 60 minutes, and poured onto ice.
  • the resultant aqueous mixture is treated with concentrated hydrochloric acid (50 mL) and extracted with methylene chloride.
  • Ammonium hydroxide (350 mL of a 30% solution, 270 mmol) is added to a mixture of 2 ' -chloro-2-methoxy-5- methyl-5 ' -nitrobenzophenone (68.7 g, 22.5 mmol) and sulfur (7.57 g, 23.6 mmol) in N,N-dimethylformamide .
  • the resultant reaction mixture is stirred at 80 °C for 19.5 hours, cooled to 40 °C, treated with additional ammonium hydroxide (50 mL of a 30% solution) , stirred at 80 °C for 25 hours, cooled, and poured onto ice.
  • the resultant aqueous mixture is filtered to obtain the title product as a yellow solid (63.5 g, 93.9%) which is identified by NMR spectral analyses .
  • the slurry is treated with 80 g of 50% sodium hydroxide solution, stirred at 60 °C to 80 °C over one hour, cooled, and decanted to obtain a residue .
  • a mixture of the residue in ethanol is treated with potassium hydroxide (10 g) , heated overnight, cooled to room temperature, neutralized with hydrochloric acid, and concentrated in vacuo to obtain a residue .
  • the residue is diluted with ethyl acetate and filtered.
  • the filtrate is concentrated in vacuo and chromatographed using silica gel and a 2% ethyl acetate in methylene chloride solution to give the title products as semi-solids which are identified by elemental and mass spectral analyses .
  • m-Fluorophenyl acetate (123 g, 0.798 mol) is cooled with an ice-bath, treated portionwise with aluminum chloride (150 g, 1.12 mol), stirred at 190 °C for one hour, and cooled to obtain a solid. A mixture of ice, water and hydrochloric acid, and methylene chloride are added to the solid. The resultant mixture is stirred for several minutes, and the phases are separated. The organic phase is washed sequentially with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title product (99.0 g) which is identified by X H NMR spectral analysis.
  • a mixture of 6-fluoro-3 -methyl-1, 2-benzisoxazole (23.5 g, 0.156 mol) in concentrated sulfuric acid is cooled with an ice-bath, treated dropwise with 90% nitric acid (8.50 mL) while maintaining the reaction mixture temperature below 15 °C, stirred for one hour at ice-bath temperature, treated with additional 90% nitric acid (5.80 mL) , warmed to and stirred at room temperature overnight, and poured onto ice.
  • the resultant aqueous mixture is filtered to obtain a solid.
  • the solid is air- dried and dissolved in methylene chloride.
  • the resultant organic solution is dried over anhydrous magnesium sulfate, diluted with hexanes, and filtered to give the title product as a purple solid which is identified by X H NMR spectral analysis.
  • a mixture of 5-nitro-l, 2-benzisoxazol-3-ol (4.00 g, 0.0220 mol) and phosphorus oxychloride (40.0 mL, 65.8 g, 0.429 mol) is placed in a glass bomb, heated at 150-155 °C for two hours, cooled overnight, concentrated in vacuo, diluted with methylene chloride, and brought to about pH 8 with sodium hydrogen carbonate solution.
  • the phases are separated.
  • the organic phase is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a residue.
  • a solution of chromium (VI) oxide (91.0 g, 0.919 mol) in a water/acetic acid solution (1:4) is added portionwise to 2-chloro-2 ' -methoxy-5-nitrobenzhydrol (64.2 g, 0.219 mol) while maintaining the reaction mixture temperature at 25 °C to 35 °C.
  • the reaction mixture is then stirred at 25 °C to 35 °C for one hour, cooled, diluted with water, and concentrated in vacuo to obtain a residue.
  • the residue is diluted with water, and extracted with methylene chloride .
  • the organic extracts are combined, dried over anhydrous sodium sulfate, mixed with silica gel (10 g) , and filtered.
  • the filtrate is concentrated in vacuo to obtain an oil .
  • a solution of the oil in a methanol/water solution is decolorized with charcoal and concentrated in vacuo to yield a residue.
  • Flash column chromatography of the solid using silica gel and a 10% to 50% ethyl acetate in hexanes gradient gives a yellow solid containing two components. Flash column chromatography of the yellow solid using silica gel and a 50% to 70% methylene chloride in hexanes gradient gives the title product as a pale, yellow solid (0.870 g, mp
  • a mixture of 2-chloro-5-nitrobenzoic acid (100 g, 0.496 mol) in ethanol is treated portionwise with potassium tert-butoxide (55.5 g, 0.495 mol), diluted with additional ethanol, heated to reflux, treated portionwise with a solution prepared from sodium sulfide nonahydrate (60.0 g, 0.249 mol), sulfur (8.80 g, 0.274 mol) and water, refluxed for two hours, cooled to room temperature, and treated with concentrated hydrochloric acid.
  • the resultant acidic mixture is stirred for one hour and filtered to obtain a solid.
  • the solid is washed with water and air-dried to give the title product as a yellow powder which is identified by NMR spectral analysis .
  • a sodium ethoxide solution (previously prepared from ethanol and sodium (1.00 g, 0.0430 mol)) is cooled with an ice-acetone bath, treated portionwise with ethyl cyanoacetate (4.51 g, 0.0398 mol), stirred at room temperature for 30 minutes, treated with 3-chloro-5- nitro-1, 2-benzisothiazole (4.27 g, 0.0199 mol), stirred at room temperature overnight, cooled to 0 °C, and treated dropwise with 10% hydrochloric acid (15.0 mL) . The resultant aqueous mixture is stirred at room temperature for one hour and filtered to obtain a solid. The solid is washed with ethanol and air-dried to give the title product as a yellow solid which is identified by NMR spectral analysis .
  • OCH 2 H CH 2 OCH 2 C ⁇ CH 115 - 117
  • a suspension of 5-nitro-l, 2 -benzisothiazole (271 g, 1.50 mol) in acetic acid is heated to 80 °C to form a solution.
  • the heating source is removed and chlorine gas is added continuously over six hours at 70-80 °C until saturation of the mixture occurs .
  • the mixture is cooled to room temperature and stirred overnight . Filtration affords the title compound as a yellow crystalline solid (237 g, 73.6%) which is identified by NMR spectral analysis .
  • Ammonium hydroxide (330 ml) is added to a suspension of 2 ' , 4 ' -difluoro-2 -methoxy-5 -methyl-5 ' -nitrobenzophenone (60.0 g, 0.186 mol), sulfur (6.25 g, 0.195 mol) and N,N- dimethylformamide on an ice bath.
  • the resultant mixture is allowed to warm to 35 °C, heated gradually to 81 °C over a two hour period, cooled to room temperature, and poured into water.
  • the resultant solid is taken up in ethyl acetate and N,N-dimethylformamide, and washed with water.
  • the organic layer is concentrated in vacuo to afford the title compound which is identified by NMR spectral analysis.

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

Abstract

Cette invention concerne un procédé amélioré de fabrication de composés 6-(perfluoroalkyl) uracil possédant la formule structurelle (I) de composées de l'urée représentés par la formule structurelle (II).
EP00910177A 1999-02-16 2000-02-14 Fabrication de composes 6-(perfluoroalkyl) uracil a partir de composes d'uree Withdrawn EP1171427A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US25095999A 1999-02-16 1999-02-16
US250959 1999-02-16
PCT/US2000/003797 WO2000049004A1 (fr) 1999-02-16 2000-02-14 Fabrication de composes 6-(perfluoroalkyl) uracil a partir de composes d'uree

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AU3231500A (en) 2000-09-04
CA2363000A1 (fr) 2000-08-24
IL144882A0 (en) 2002-06-30
HUP0201513A2 (en) 2002-08-28
JP4619544B2 (ja) 2011-01-26
RU2001124602A (ru) 2004-03-20
CN1344260A (zh) 2002-04-10
JP2002537291A (ja) 2002-11-05
WO2000049004A1 (fr) 2000-08-24
KR20010114208A (ko) 2001-12-31
MXPA01008189A (es) 2004-09-06

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