3-amino-1,1-dimethylthiourea

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4.16 g (0.035 mole) of 4,4-dimethyl-thiosemicarbazide and 7.82 g (0.035 mole) of 2,4-dichlorophenacyl chloride are reacted under the conditions of Example 2. After concentration, ethyl acetate is added to the residue and further concentration is employed. A yellow, needle-like solid is produced. The solid is dried under high vacuum at 65° C. Subsequently, it is recrystallized from methanol/ethyl acetate and again dried under high vacuum to produce 5-(2,4-dichlorophenyl)-N,N-dimethyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride. m.p. 219°-222° C. After concentration, ethyl acetate is added to the residue and further concentration A yellow, needle-like solid is produced The solid is dried under high vacuum at 65° C Subsequently, it is recrystallized from methanol/ethyl acetate again dried under high vacuum

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4,4-dimethylthiosemicarbazide (2.70 g, 0.022 mol) and 2,6-diacetylpyridine (1.63 g, 0.10 mol) in 95% EtOH (45 ml) containing glacial acetic acid (0.5 ml) was heated by a steam bath for 1 h and 10 min and allowed to cool to ambient temperature. The yellow precipitate was collected by filtration, washed with 95% EtOH, and subsequently recrystallized from toluene: yield 2.72 g (73%); mp 215° (dec). was heated by a steam bath for 1 h and 10 min The yellow precipitate was collected by filtration washed with 95% EtOH subsequently recrystallized from toluene

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4,4-dimethylthiosemicarbazide (2.70 g, 0.022 mol) and 2,6-diacetylpyridine (1.63 g, 0.10 mol) in 95% EtOH (45 ml) containing glacial acetic acid (0.5 ml) was heated by a steam bath for 1 h and 10 min and allowed to cool to ambient temperature. The yellow precipitate was collected by filtration, washed with 95% EtOH, and subsequently recrystallized from toluene: yield 2.72 g (73%); mp 215° (dec). was heated by a steam bath for 1 h and 10 min The yellow precipitate was collected by filtration washed with 95% EtOH subsequently recrystallized from toluene

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred slurry of 2.5 g (0.013 mole) of 4,4-dimethyl-3-thiosemicarbazide in 50 mL of absolute ethanol was treated with 2.1 g (0.013 mole) of ethyl 2-chloroacetoacetate added at a rapid rate under nitrogen atmosphere. The reaction mixture turned yellow immediately, cleared, became cloudy and finally became a clear orange solution within 5 minutes. The reaction mixture was stirred at ambient temperature for ~72 hr, heated to reflux, filtered hot, and concentrated in vacuo to give a yellow oil which solidified. Trituration with benzene gave 3 g of tan solid. After 3 recrystallizations from benzene, 1.8 g of fine pale beige crystalline product was obtained, mp 135°-139° C. After drying at 98° C. under reduced pressure for 3 hr, mp 137-139° C. Analysis: Calculated for C9H16ClN3O2 : C, 46.26; H, 6.90; N, 17.98. Found: C, 46.05; H, 6.91; N, 18.09. added at a rapid rate under nitrogen atmosphere within 5 minutes heated to reflux filtered hot concentrated in vacuo to give a yellow oil which

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred slurry of 2.5 g (0.013 mole) of 4,4-dimethyl-3-thiosemicarbazide in 50 mL of absolute ethanol was treated with 2.1 g (0.013 mole) of ethyl 2-chloroacetoacetate added at a rapid rate under nitrogen atmosphere. The reaction mixture turned yellow immediately, cleared, became cloudy and finally became a clear orange solution within 5 minutes. The reaction mixture was stirred at ambient temperature for ~72 hr, heated to reflux, filtered hot, and concentrated in vacuo to give a yellow oil which solidified. Trituration with benzene gave 3 g of tan solid. After 3 recrystallizations from benzene, 1.8 g of fine pale beige crystalline product was obtained, mp 135°-139° C. After drying at 98° C. under reduced pressure for 3 hr, mp 137-139° C. Analysis: Calculated for C9H16ClN3O2 : C, 46.26; H, 6.90; N, 17.98. Found: C, 46.05; H, 6.91; N, 18.09. added at a rapid rate under nitrogen atmosphere within 5 minutes heated to reflux filtered hot concentrated in vacuo to give a yellow oil which

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred slurry of 2.5 g (0.013 mole) of 4,4-dimethyl-3-thiosemicarbazide in 50 mL of absolute ethanol was treated with 2.1 g (0.013 mole) of ethyl 2-chloroacetoacetate added at a rapid rate under nitrogen atmosphere. The reaction mixture turned yellow immediately, cleared, became cloudy and finally became a clear orange solution within 5 minutes. The reaction mixture was stirred at ambient temperature for ~72 hr, heated to reflux, filtered hot, and concentrated in vacuo to give a yellow oil which solidified. Trituration with benzene gave 3 g of tan solid. After 3 recrystallizations from benzene, 1.8 g of fine pale beige crystalline product was obtained, mp 135°-139° C. After drying at 98° C. under reduced pressure for 3 hr, mp 137-139° C. Analysis: Calculated for C9H16ClN3O2 : C, 46.26; H, 6.90; N, 17.98. Found: C, 46.05; H, 6.91; N, 18.09. added at a rapid rate under nitrogen atmosphere within 5 minutes heated to reflux filtered hot concentrated in vacuo to give a yellow oil which

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 4,4-dimethyl-3-thiosemicarbazide (2.0 g, 16.8 mmol) and ethyl chloro-oxo-acetate (2.3 g, 16.8 mmol) were mixed under an inert atmosphere and cooled to 0° C. in an ice bath. Sulfuric acid (2 mL) was added slowly. After the effervescence ceased, the ice bath was removed and the reaction was allowed to warm to room temperature and stirred for 3 hours. To the white heterogeneous mixture, ethyl acetate (100 mL) was added and the organic layer was washed twice with 2% sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residual solid was dissolved in ethyl acetate and the desired compound was precipitated with ether to yield the ethyl 5-(dimethylamino)-1,3,4-thiadiazole-2-carboxylate (IIIc) (1.9 g, 9.4 mmol). The ester, (IIIc) was dissolved in anhydrous methyl acetate (4 mL) and solution purged with an inert atmosphere. To this yellow solution sodium hydride (60% dispersion in mineral oil, 0.53 g, 13.25 mmol) was added providing a light yellow precipitate. The reaction mixture was then heated to 65° C. and it turned to a light green precipitate. Additional methyl acetate (4 mL) was added and in ten minutes the reaction mixture became a tan solid. The reaction was removed from the heat and an additional methyl acetate (20 mL) was added. The mixture was neutralized with acetic acid. The solid was filtered off and the filtrate was evaporated. The solid from the filtrate was washed with ether to yield the desired β-ketoester, ethyl 3-[5-(dimethylamino)(1,3,4-thiadiazol-2-yl)]-3-oxopropanoate, (Vd) (5.2 mmol) as a yellow solid. A mixture of the β-ketoester (Vd) (1.2 g, 1.31 mmol), ethanol (2 mL) and hydrazine hydrate (0.063 g, 1.96 mmol) was heated to 65° C. for two hours. The precipitate was filtered to obtain the pyrazolone (VIi) (0.075 g, 0.36 mmol) as a light yellow solid. the ice bath was removed to warm to room temperature To the white heterogeneous mixture, ethyl acetate (100 mL) was added the organic layer was washed twice with 2% sodium bicarbonate solution and brine The organic layer was dried over anhydrous magnesium sulfate evaporated The residual solid was dissolved in ethyl acetate the desired compound was precipitated with ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 11.7 g (0.041 mol) of 2-bromo-1-(5-tert.butyl)-3-methyl-4-hydroxyphenyl)-ethanone from step (a) and 4.4 g (0.037 mol) of 4,4-dimethylthiosemicarbazide in 130 ml of ethanol was refluxed briefly. After cooling, the reaction mixture was worked up corresponding to Example 1(b). After cooling

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 196.4 g (0.6 mol) of 2-bromo-1-(3,5-di-tert.butyl-4-hydroxyphenyl)-ethanone from step (a) and 59.6 g (0.5 mol) of 4,4-dimethylthiosemicarbazide were suspended in 1500 ml of ethanol and slowly heated to 70° C. while stirring, a clear solution being produced. The solution was stirred at this temperature for 10 minutes and then cooled, and the solvent was removed under reduced pressure. Washing the residue, produced as an oil, by stirring with 500 ml of ethyl acetate produced a batch of crystals, which was again briefly heated to boiling in 500 ml of ethyl ester. The crystalline product was filtered off, washed with 150 ml of ethyl acetate and dried in a vacuum cabinet. a clear solution being produced The solution was stirred at this temperature for 10 minutes cooled the solvent was removed under reduced pressure Washing the residue produced as an oil produced a batch of crystals, which was again briefly heated The crystalline product was filtered off washed with 150 ml of ethyl acetate dried in a vacuum cabinet

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred slurry of 2.5 g (0.013 mole) of 4,4-dimethyl-3-thiosemicarbazide in 50 mL of absolute ethanol was treated with 2.1 g (0.013 mole) of ethyl 2-chloroacetoacetate added at a rapid rate under nitrogen atmosphere. The reaction mixture turned yellow immediately, cleared, became cloudy and finally became a clear orange solution within 5 minutes. The reaction mixture was stirred at ambient temperature for ~72 hr, heated to reflux, filtered hot, and concentrated in vacuo to give a yellow oil which solidified. Trituration with benzene gave 3 g of tan solid. After 3 recrystallizations from benzene, 1.8 g of fine pale beige crystalline product was obtained, mp 135°-139° C. After drying at 98° C. under reduced pressure for 3 hr, mp 137°-139° C. added at a rapid rate under nitrogen atmosphere within 5 minutes heated to reflux filtered hot concentrated in vacuo to give a yellow oil which

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 4,4-dimethyl-3-thiosemicarbazide (2.0 g, 16.8 mmol) and ethyl chloro-oxo-acetate (2.3 g, 16.8 mmol) were mixed under an inert atmosphere and cooled to 0° C. in an ice bath. Sulfuric acid (2 mL) was added slowly. After the effervescence ceased, the ice bath was removed and the reaction was allowed to warm to room temperature and stirred for 3 hours. To the white heterogeneous mixture, ethyl acetate (100 mL) was added and the organic layer was washed twice with 2% sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residual solid was dissolved in ethyl acetate and the desired compound was precipitated with ether to yield the ethyl 5-(dimethylamino)-1,3,4-thiadiazole-2-carboxylate (IIIc) (1.9 g, 9.4 mmol). The ester, (IIIc) was dissolved in anhydrous methyl acetate (4 mL) and solution purged with an inert atmosphere. To this yellow solution sodium hydride (60% dispersion in mineral oil, 0.53 g, 13.25 mmol) was added providing a light yellow precipitate. The reaction mixture was then heated to 65° C. and it turned to a light green precipitate. Additional methyl acetate (4 mL) was added and in ten minutes the reaction mixture became a tan solid. The reaction was removed from the heat and an additional methyl acetate (20 mL) was added. The mixture was neutralized with acetic acid. The solid was filtered off and the filtrate was evaporated. The solid from the filtrate was washed with ether to yield the desired β-ketoester, ethyl 3-[5-(dimethylamino)(1,3,4-thiadiazol-2-yl)]-3-oxopropanoate, (Vd) (5.2 mmol) as a yellow solid. A mixture of the β-ketoester (Vd) (1.2 g, 1.31 mmol), ethanol (2 mL) and hydrazine hydrate (0.063 g, 1.96 mmol) was heated to 65° C. for two hours. The precipitate was filtered to obtain the pyrazolone (VIi) (0.075 g, 0.36mmol) as a light yellow solid. the ice bath was removed to warm to room temperature To the white heterogeneous mixture, ethyl acetate (100 mL) was added the organic layer was washed twice with 2% sodium bicarbonate solution and brine The organic layer was dried over anhydrous magnesium sulfate evaporated The residual solid was dissolved in ethyl acetate the desired compound was precipitated with ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4.16 g (0.035 mole) of 4,4-dimethyl-thiosemicarbazide and 7.82 g (0.035 mole) of 2,4-dichlorophenacyl chloride are reacted under the conditions of Example 2. After concentration, ethyl acetate is added to the residue and further concentration is employed. A yellow, needle-like solid is produced. The solid is dried under high vacuum at 65° C. Subsequently, it is recrystallized from methanol/ethyl acetate and again dried under high vacuum to produce 5-(2,4-dichlorophenyl)-N,N-dimethyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride. m.p. 219°-222° C. After concentration, ethyl acetate is added to the residue and further concentration A yellow, needle-like solid is produced The solid is dried under high vacuum at 65° C Subsequently, it is recrystallized from methanol/ethyl acetate again dried under high vacuum