ethyl N,N-dichlorocarbamate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 15.7 g cyclododecene and 15.8 g dichlorourethane in 125 ml of benzene was refluxed for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled, diluted with 100 ml of ether and then washed repeatedly with saturated sodiumbisulfite solution. After washing with brine the organic layer was dried and concentrated to give 19.5 g of crudechlorourethane. This was heated at 100°-120° C. for 6 hours. The resulting thick dark oil was diluted with hexane and allowed to stand in the freezer overnight. The solid was filtered and recrystallized from hexane/dichloromethane to give 5.66 g of white crystals, m.p. 84°-86° C. The mother liquor was concentrated to give 5.23 g of thick oil which after flash chromatography (silica gel; ethyl acetate/hexane) gave additional 1.23 g of white crystals, m.p. 85° C. and 0.96 g of a clear oil, which slowly solidified. Recrystallization from hexane gave 0.25 g of crystals, m.p. 72°-74° C. The reaction mixture was cooled washed repeatedly with saturated sodiumbisulfite solution After washing with brine the organic layer was dried concentrated to give 19.5 g of crudechlorourethane This was heated at 100°-120° C. for 6 hours to stand in the freezer overnight The solid was filtered recrystallized from hexane/dichloromethane

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 11.54 g of 3,3,4-trichloro-5-methoxy-1 ,3-dihydro-indol-2-one (43.3 mmol) was suspended in glacial AcOH (200 mL). 3.343 g (21.7 mmol) of N,N-dichlorourethane was added and the mixture was stirred at 60° C. for 2 days. The reaction mixture was cooled to room temperature, the precipitate collected by filtration and dried on high vacuum. Re-crystallization from benzene (150 mL) yielded 6.135 g of product (containing 5% of the start. material as an impurity). The reaction mixture was cooled to room temperature the precipitate collected by filtration dried on high vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred solution of 0.84 gram (2.1 mmole) of 3-(2-t-butyl-4-chlorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione (prepared as described in Example 2) in 20 mL of acetic acid had 0.16 gram (1.0 mmole) of N,N-dichlorourethane added via syringe. Upon completion of the addition the clear reaction mixture was stirred for 15 minutes, then one drop of concentrated hydrochloric acid was added, and the reaction mixture was stirred at ambient temperature for 72 hours. After this time the reaction mixture was poured into 100 mL of water, and 10 grams of sodium carbonate were added. The mixture was extracted with three 50 mL portions of methylene chloride. The organic extracts were combined and washed with one 50 mL portion of an aqueous 5% sodium carbonate solution. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrate under reduced pressure, yielding a pale yellow oil which was subjected to column chromatography on silica gel. Elution was accomplished with 9:1 heptane:ethyl acetate, followed by 2:1 heptane:ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.57 gram of 3-(2-t-butyl-4-chlorobenzoxazol-7-yl)-1-methyl-5-chloro-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione, m.p. 83°-86° C. The NMR spectrum was consistent with the proposed structure. added via syringe Upon completion of the addition the clear reaction mixture the reaction mixture was stirred at ambient temperature for 72 hours were added The mixture was extracted with three 50 mL portions of methylene chloride washed with one 50 mL portion of an aqueous 5% sodium carbonate solution The organic layer was dried with sodium sulfate filtered The filtrate was concentrate under reduced pressure yielding a pale yellow oil which Elution concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under a nitrogen atmosphere, a solution of 3.1 grams (11.0 mmole) of ethyl N-(2-t-butyl-6-fluorobenzoxazol-7-yl)carbamate, 35 mL of acetic acid, and 0.2 mL (2.4 mmole) of concentrated hydrochloric acid was stirred and cooled in an ice bath. During five minutes 2.2 grams (14 mmole) of N,N-dichlorourethane was added via syringe. Upon completion of the addition the reaction mixture was stirred for 4 hours, then analyzed by TLC, which indicated the reaction was complete. The reaction mixture was poured into 100 mL of water, and 15 mL of aqueous saturated sodium bicarbonate solution was carefully added. The reaction mixture was then extracted with two 75 mL portions of diethyl ether, and the combined extracts were concentrated under reduced pressure, yielding a residual oil. The oil was subjected to column chromatography on silica gel with 8:1 hexane:ethyl acetate as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 2.4 grams of ethyl N-(2-t-butyl-4-chloro-6-fluorobenzoxazol-7-yl)carbamate, m.p. 127°-129° C. The NMR spectrum was consistent with the proposed structure. cooled in an ice bath Upon completion of the addition the reaction mixture was carefully added The reaction mixture was then extracted with two 75 mL portions of diethyl ether the combined extracts were concentrated under reduced pressure yielding a residual oil concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: At this point additional substituents may be optionally added to the pyrimidinedione ring. For example, a chlorine moiety was added to the 3-(2-t-butyl-4-chlorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione molecule (I) by treating it with N,N-dichlorourethane under acidic conditions, affording 3-(2-t-butyl-4-chlorobenzoxazol-7-yl)-1-methyl-5-chloro-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (III). In addition, the 3-[2-(substituted-methoxyalkyl)-substituted-benzoxazol-7-yl]-1-alkyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (I), for example 3-[2-(1-methoxy-1-methylethyl)-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione, can be hydrogenated under basic conditions, yielding the targeted 3-[2-(substituted-hydroxyalkyl)-substituted-benzoxazol-7-yl)-1-alkyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (IV), for example 3-[2-(1-hydroxy-1-methylethyl)-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione. Examples 3 and 15 provide the detailed procedures for these methods. At this point additional substituents may be optionally added to the pyrimidinedione ring

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The second starting material used to prepared those compounds in which the benzoxazole ring is formed first is a substituted-3-chloroaniline (STM2). The aniline (STM2) is reacted with the appropriate alkyl anhydride, for example trimethylacetic anhydride, under acidic conditions, yielding the corresponding N-(substituted-3-chlorophenyl)alkylamide (B-1). The aniline (STM2) can also be reacted with the appropriate propanoic acid (A-2), for example 2-methoxy-2-methylpropanoic acid, under basic conditions to form the appropriate N-(substituted-3-chlorophenyl)-substituted-alkylpropion-amide (B-2), for example N-(3-chloro-4-fluorophenyl)-2-methoxy-2-methyl-propionamide. The amides (B-1 or B-2) are in turn treated with n-butyl-lithium and cyclized with solid carbon dioxide, affording the corresponding [2-alkyl- or 2-(substituted-alkyl)-substituted-benzoxazol-7-yl]carboxylic acid (C), for example, (2-t-butyl-6-fluorobenzoxazol-7-yl)carboxylic acid. The so-prepared carboxylic acid (C) is then reacted with ethyl chloroformate, 4-methylmorpholine, and sodium azide, yielding the corresponding [2-alkyl- or 2-(substituted-alkyl)-substituted-benzoxazol-7-yl]carbonyl azide (C-1), which is treated with ethanol to form the corresponding ethyl N-[2-alkyl- or 2-(substituted-alkyl)-substituted-benzoxazol-7-yl]carbamate (D). Additional substituents may optionally be added to the benzoxazole ring at this point. For example, ethyl N-(2-t-butyl-6-fluorobenzoxazol-7-yl)carbamate (D) is treated with N,N-dichlorourethane under acidic conditions, affording ethyl N-(2-t-butyl-4-chloro-6-fluorobenzoxazol-7-yl)carbamate (E). The carbamates D and E are then reacted with ethyl 3-amino-4,4,4-trifluorocrotonate, sodium methoxide, and DBU to form the corresponding 3-[2-alkyl- or 2-(substituted-alkyl)-substituted-benzoxazol-7-yl]-6-trifluoromethyl-2,4-(1H,3H)-pyrimidine-dione (F). The pyrimidinedione (F) is further reacted under basic conditions with an alkyl halide, for example methyl iodide, or O-(2,4-dinitrophenyl)hydroxylamine, or 1-aminooxysulfonyl-2,4,6-trimethylbenzene, affording the targeted 3-[2-alkyl- or 2-(substituted-alkyl)-substituted-benzoxazol-7-yl]-1-alkyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (I) or 3-[2-alkyl- or 2-(substituted-alkyl)-substituted-benzoxazol-7-yl]-1-amino-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (II). Examples 1, 2, 4, and 5 provide the detailed procedures for this route. Additional substituents may optionally be added to the benzoxazole ring at this point

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 15.7 g cyclododecene and 15.8 g dichlorourethane in 125 ml of benzene was refluxed for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled, diluted with 100 ml of ether and then washed repeatedly with saturated sodiumbisulfite solution. After washing with brine the organic layer was dried and concentrated to give 19.5 g of crudechlorourethane. This was heated at 100°-120° C. for 6 hours. The resulting thick dark oil was diluted with hexane and allowed to stand in the freezer overnight. The solid was filtered and recrystallized from hexane/dichloromethane to give 5.66 g of white crystals, m.p. 84°-86° C. The mother liquor was concentrated to give 5.23 g of thick oil which after flash chromatography (silica gel; ethyl acetate/hexane) gave additional 1.23 g of white crystals, m.p. 85° C. and 0.96 g of a clear oil, which slowly solidified. Recrystallization from hexane gave 0.25 g of crystals, m.p. 72°-74° C. The reaction mixture was cooled washed repeatedly with saturated sodiumbisulfite solution After washing with brine the organic layer was dried concentrated to give 19.5 g of crudechlorourethane This was heated at 100°-120° C. for 6 hours to stand in the freezer overnight The solid was filtered recrystallized from hexane/dichloromethane

Conditions: temp:0.00; pressure:0.00; stir: