1,3-dimethylthiourea

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 1,3-dimethylthiourea (2.489 g, 23.89 mmol) and triethylamine (2.78 ml, 19.91 mmol) in dry toluene was added 2,2,7-trifluoro-6-isocyanato-4-(prop-2-ynyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (5.62 g, 19.91 mmol) in dry toluene. Hereto was subsequently added carbonyldiimidazole (CDI; 6.46 g, 39.8 mmol) and the resulting mixture was stirred at 80° C. overnight. Then the reaction mixture was cooled to room temperature and poured into ethyl acetate/water under stirring. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined extracts were washed with brine, dried with Na2SO4 and concentrated to yield 14.4 g. Then the reaction mixture was cooled to room temperature under stirring The layers were separated the aqueous layer was extracted with dichloromethane The combined extracts were washed with brine dried with Na2SO4 concentrated to yield 14.4 g

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 3.0 g (15.0 mmol) of diphosgene in 5 ml of toluene was added dropwise at approximately 20° C. to a solution of 3.0 g (13.6 mmol) of 4-chloro-6-fluoro-2-methoxy-3-nitrophenylamine in 15 ml of toluene. Then, the mixture was slowly heated to reflux temperature and stirred for 6 hours under reflux. After the reaction mixture had been concentrated and dried, the crude isocyanate was redissolved in 5 ml of toluene to be used in the next reaction. 6 ml of triethylamine and a solution of 3.55 g (14.4 mmol) of dimethylthiourea were added dropwise to this solution at approximately 20° C. 4.7 g (28.8 mmol) of carbonyldiimidazole were subsequently added to the reaction mixture. The mixture was heated at 80° C. for 5 hours and then allowed to cool. For work-up, it was firstly washed four times with water. Then, the organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The crude product (6.58 g) was purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate=10:1). Yield: 1.31 g (24%); Then, the mixture was slowly heated to reflux temperature under reflux After the reaction mixture had been concentrated dried the crude isocyanate was redissolved in 5 ml of toluene to be used in the next reaction to cool For work-up, it was firstly washed four times with water Then, the organic phase was dried over magnesium sulfate concentrated under reduced pressure The crude product (6.58 g) was purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate=10:1)

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3 ml of triethylamine and then a solution of 22.4 g (91.2 mmol) of 4-chloro-2-fluoro-5-(methoxycarbonyloxy)phenyl isocyanate in 100 ml of toluene were added dropwise at approximately 20° C. to a solution of 9.5 g (91.2 mmol) of N,N′-dimethylthiourea in 20 ml of toluene. After addition of 29.6 g (182.5 mmol) of carbodiimidazole, the mixture was heated for 3 hours at 80° C. The reaction mixture was stirred overnight at approximately 20° C., then washed three times with water and finally concentrated under reduced pressure. The crude product was purified by column chromatography (mobile phase: cyclohexane/ethyl acetate=10:1). Yield: 18.1 g (63%); m.p.: 242-246° C. washed three times with water finally concentrated under reduced pressure The crude product was purified by column chromatography (mobile phase: cyclohexane/ethyl acetate=10:1)

反応条件: temp:62.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 31 g of 2,4-difluorophenyl isocyanate and 64.9 g of carbodiimidazole were added in succession to 20.8 g of N,N′-dimethylthiourea in 500 ml of toluene and 1 ml of triethylamine. This mixture was stirred first for 3 hours at 60-65° C. and then for 12 hours at 80-85° C. After cooling to room temperature, the mixture was washed three times with 100-ml-portions of water, and the organic phase was dried over sodium sulfate. After distillation of the low-boiling fractions, 48 g of the desired product of melting point 156-159° C. remained. for 12 hours at 80-85° C After cooling to room temperature the mixture was washed three times with 100-ml-portions of water the organic phase was dried over sodium sulfate After distillation of the low-boiling fractions, 48 g of the desired product of melting point 156-159° C.

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

実験手順: Similarly, 2.7 g (0.02 mole) of N-methylene-2,6-dimethylaniline, 2.0 g of trichloromethyl chloroformate, 2.0 g (0.02 mole) of 1,3-dimethylthiourea, and 18 g of a 10% aqueous sodium hydroxide solution were used to obtain 0.6 g (12% yield) of 2-methylimino-3-methyl-5-(2,6-dimethylphenyl)-tetrahydro-1,3,5-thiadiazin-4-one (compound No. 389) of the formula, ##STR179## as a colorless oily substance (nD20 1.5967).

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 g (0.02 mole) of N-benzyl-N-chloromethylcarbamoyl chloride and 2.0 g (0.02 mole) of 1,3-dimethylthiourea was dissolved in 50 ml of ethyl alcohol and heated under reflux with stirring for 2 hours. After addition of 20 ml of a saturated aqueous potassium carbonate solution, the mixture was extracted with 100 ml of benzene. The benzene layer was washed with water, dried, and freed from the benzene by distillation under reduced pressure to obtain 4.0 g of crude crystals which were recrystallized from ether. Yield 3.2 g (63%); m.p. 93°-95° C. heated under reflux the mixture was extracted with 100 ml of benzene The benzene layer was washed with water dried freed from the benzene by distillation under reduced pressure

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

実験手順: In 50 ml of toluene, were dissolved 3.7 g (0.02 mole) of N-t-butyl-N-chloromethylcarbamoyl chloride and 2.0 g (0.02 mole) of 1,3-dimethylthiourea. The solution was heated under reflux with stirring for one hour. After cooling, the precipitated crystals (m.p. >220° C. decomp.) were collected by filtration, washed with a small quantity of acetone, dissolved again in 100 ml of water, admixed with 10 ml of a 20% sodium hydroxide solution, and extracted with 50 ml of benzene. The benzene layer was dried and concentrated under reduced pressure to obtain 3.5 g (83% yield) of crystals melting at 51°-52° C. The solution was heated under reflux After cooling the precipitated crystals (m.p. >220° C. decomp.) were collected by filtration washed with a small quantity of acetone dissolved again in 100 ml of water extracted with 50 ml of benzene The benzene layer was dried concentrated under reduced pressure

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

実験手順: tert-Butyl 4-(1-bromo-2-oxoethyl)piperidine-1-carboxylate (WO 0059502: 21.0 g) and a solution of N,N′-dimethylthiourea (6.0 g) in ethanol (300 mL) were heated under reflux. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate and water. The aqueous layer was collected by separation. The aqueous layer was basified with an aqueous potassium carbonate solution, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off to give the title compound (12.2 g) as a pale yellow solid. under reflux The reaction solution was concentrated the residue was dissolved in ethyl acetate The aqueous layer was collected by separation extracted with chloroform The extract was dried over anhydrous sodium sulfate the solvent was distilled off

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

実験手順: tert-Butyl 4-(1-bromo-2-oxoethyl)piperidine-1-carboxylate (WO 0059502: 21.0 g) and a solution of N,N′-dimethylthiourea (6.0 g) in ethanol (300 mL) were heated under reflux. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate and water. The aqueous layer was collected by separation. The aqueous layer was basified with an aqueous potassium carbonate solution, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off to give the title compound (12.2 g) as a pale yellow solid. under reflux The reaction solution was concentrated the residue was dissolved in ethyl acetate The aqueous layer was collected by separation extracted with chloroform The extract was dried over anhydrous sodium sulfate the solvent was distilled off

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

実験手順: 4.8 g of 2,4'-dichloro-3'-dipropylsulfamoylacetophenone and 1.5 g of 1,3-dimethylthiourea were reacted as prescribed in Example 23 and worked up. Colorless crystals, melting point: 166° C (decomposition).

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

実験手順: 4.8g of 3'-diethylsulfamoyl-2,4'-dichloroacetophenone and 1.5 g of 1,3-dimethylthiourea were reacted as prescribed in Example 23 and the crystalline end product was filtered off. Melting point: 165° C (decomposition). the crystalline end product was filtered off

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

実験手順: 5.2 g of 2-bromo-4'-chloro-3'-phenylsulfamoylacetophenone and 1.5 g of 1,3-dimethylthiourea were reacted as prescribed in Example 23 and the precipitated end product was filtered off. Colorless crystals, melting point: 82° C (decomposition). the precipitated end product was filtered off