4-(chloromethyl)-2-[(dimethylamino)methyl]-5H-1,3-thiazol-4-ol

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

実験手順: To a 100 ml. flask were added 2.1 g. of 4-chloromethyl-4-hydroxy-2-dimethylaminomethyl-2-thiazoline and 25 ml. of 1,2-dichloroethane. To the mixture was added dropwise a solution of 2.1 g. of phosphorous pentachloride and 50 ml. of 1,2-dichloroethane, while the temperature of the mixture was held in the range 17°-25°. After the addition, the mixture was stirred for 16 hours. It was then filtered, and the filter cake was washed with 1,2-dichloroethane and dried under vacuum at 50° to obtain 2.4 g. of the desired product, which was identified by nmr analysis as being substantially identical to the product of Example 5. flask were added 2.1 g To the mixture was added dropwise a solution of 2.1 g was held in the range 17°-25° After the addition It was then filtered the filter cake was washed with 1,2-dichloroethane dried under vacuum at 50° to obtain 2.4 g

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

実験手順: A 1.9 g. portion of 4-chloromethyl-4-hydroxy-2-dimethylaminomethyl-2-thiazoline and 19 ml. of 1,2-dichloroethane were added to a 100 ml. flask, and the mixture was cooled while 1.53 g. of phosphorus oxychloride dissolved in 10 ml. of 1,2-dichloroethane was added dropwise. The mixture was stirred for 30 minutes at 23°, and then at 50° for 1 hour. It was cooled, and 25 ml. of water was added. The layers were separated, and both layers were examined by the tlc system described above in Example 1. No product or starting compound was in the organic layer. The aqueous layer contained all of the product and there was no indication of remaining starting material. flask, and the mixture was cooled while 1.53 g at 50° for 1 hour It was cooled The layers were separated

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

実験手順: Five g. of 4-chloromethyl-4-hydroxy-2-dimethylaminomethyl-2-thiazoline was added to 25 ml. of 1,2-dichloroethane, and 2.1 g. of sulfuryl chloride in 10 ml. of 1,2-dichloroethane was added. An exothermic reaction heated the mixture to 35° as soon as the addition began, so the mixture was cooled while the addition was made. The mixture was then stirred at ambient temperature for 1 hour, and was then heated to 42° for a short time. A 2-phase mixture formed, and the oily portion was removed and dissolved in 10 ml. of methanol. The methanol was removed under vacuum, and the residue was partially dissolved in 10 ml. of methanol, and then precipitated by addition of 25 ml. of ethyl acetate. The mixture was then cooled in the freezer, and the crystals were filtered off, washed with ethyl acetate and dried under vacuum at 30° to obtain 1.4 g. of the desired product, which was identified by nmr analysis as being substantially identical with the product of Example 5. An exothermic reaction heated the mixture to 35° as soon as the addition was cooled while the addition was then heated to 42° for a short time A 2-phase mixture formed the oily portion was removed dissolved in 10 ml The methanol was removed under vacuum the residue was partially dissolved in 10 ml of methanol, and then precipitated by addition of 25 ml The mixture was then cooled in the freezer the crystals were filtered off washed with ethyl acetate dried under vacuum at 30° to obtain 1.4 g

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

実験手順: Ten g. of 4-chloromethyl-4-hydroxy-2-dimethylaminomethyl-2-thiazoline was dissolved in 50 ml. of 1,2-dichloroethane, and to it was added 8.6 g. of thionyl chloride dissolved in 30 ml. of 1,2-dichloroethane. The mixture was stirred at ambient temperature overnight, and then was stirred at 35° for 35 minutes and then for 1 hour at 50°. The mixture was cooled to 5° and filtered, and the solids were washed with 1,2-dichloroethane, and then were slurried in 20 ml. of methanol and 50 ml. of ethyl acetate. The crystals were then recovered by filtration and dried to obtain 6.4 g. of relatively pure product, m.p. 137°-140°. The product was identified by nmr analysis in DMSO-D6, on a 60 mHz instrument, which analysis showed characteristic features at δ3.05 (s, 6H); 4.85 (s, 2H); 4.90 (s, 2H); 7.85 (s, 1H). was stirred at 35° for 35 minutes for 1 hour at 50° The mixture was cooled to 5° filtered the solids were washed with 1,2-dichloroethane The crystals were then recovered by filtration dried to obtain 6.4 g

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

実験手順: To a flask were added 44.5 g. of dimethylaminothioacetamide, hydrochloride, 40.4 g. of 1,3-dichloropropanone, 224 ml. of 1,2-dichloroethane and 53.4 g. of sodium bicarbonate. An endothermic reaction took place and cooled the mixture to 13° on initial mixing. The mixture was then stirred overnight at ambient temperature, and the reaction was found to be essentially complete after 24 hours, by thin layer chromatography. The tlc system is silica gel, eluting with chloroform:methanol:ammonium hydroxide, 36:4:1. The mixture was then filtered, and the filter cake was washed with 1,2-dichloroethane. The filtrate was evaporated to dryness under vacuum to obtain 59.5 g. of crude product, which was washed with ethyl acetate. The washed solids were dried in air, to obtain 52.5 g. of substantially pure product, m.p. 90°-92°. To a flask were added 44.5 g An endothermic reaction cooled the mixture to 13° on initial mixing to be essentially complete after 24 hours, by thin layer chromatography eluting with chloroform The mixture was then filtered the filter cake was washed with 1,2-dichloroethane The filtrate was evaporated to dryness under vacuum to obtain 59.5 g of crude product, which was washed with ethyl acetate The washed solids were dried in air to obtain 52.5 g

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

実験手順: To a 100 ml. flask were added 2.1 g. of 4-chloromethyl-4-hydroxy-2-dimethylaminomethyl-2-thiazoline and 25 ml. of 1,2-dichloroethane. To the mixture was added dropwise a solution of 2.1 g. of phosphorous pentachloride and 50 ml. of 1,2-dichloroethane, while the temperature of the mixture was held in the range 17°-25°. After the addition, the mixture was stirred for 16 hours. It was then filtered, and the filter cake was washed with 1,2-dichloroethane and dried under vacuum at 50° to obtain 2.4 g. of the desired product, which was identified by nmr analysis as being substantially identical to the product of Example 5. flask were added 2.1 g To the mixture was added dropwise a solution of 2.1 g was held in the range 17°-25° After the addition It was then filtered the filter cake was washed with 1,2-dichloroethane dried under vacuum at 50° to obtain 2.4 g

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

実験手順: A 1.9 g. portion of 4-chloromethyl-4-hydroxy-2-dimethylaminomethyl-2-thiazoline and 19 ml. of 1,2-dichloroethane were added to a 100 ml. flask, and the mixture was cooled while 1.53 g. of phosphorus oxychloride dissolved in 10 ml. of 1,2-dichloroethane was added dropwise. The mixture was stirred for 30 minutes at 23°, and then at 50° for 1 hour. It was cooled, and 25 ml. of water was added. The layers were separated, and both layers were examined by the tlc system described above in Example 1. No product or starting compound was in the organic layer. The aqueous layer contained all of the product and there was no indication of remaining starting material. flask, and the mixture was cooled while 1.53 g at 50° for 1 hour It was cooled The layers were separated

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

実験手順: Five g. of 4-chloromethyl-4-hydroxy-2-dimethylaminomethyl-2-thiazoline was added to 25 ml. of 1,2-dichloroethane, and 2.1 g. of sulfuryl chloride in 10 ml. of 1,2-dichloroethane was added. An exothermic reaction heated the mixture to 35° as soon as the addition began, so the mixture was cooled while the addition was made. The mixture was then stirred at ambient temperature for 1 hour, and was then heated to 42° for a short time. A 2-phase mixture formed, and the oily portion was removed and dissolved in 10 ml. of methanol. The methanol was removed under vacuum, and the residue was partially dissolved in 10 ml. of methanol, and then precipitated by addition of 25 ml. of ethyl acetate. The mixture was then cooled in the freezer, and the crystals were filtered off, washed with ethyl acetate and dried under vacuum at 30° to obtain 1.4 g. of the desired product, which was identified by nmr analysis as being substantially identical with the product of Example 5. An exothermic reaction heated the mixture to 35° as soon as the addition was cooled while the addition was then heated to 42° for a short time A 2-phase mixture formed the oily portion was removed dissolved in 10 ml The methanol was removed under vacuum the residue was partially dissolved in 10 ml of methanol, and then precipitated by addition of 25 ml The mixture was then cooled in the freezer the crystals were filtered off washed with ethyl acetate dried under vacuum at 30° to obtain 1.4 g

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

実験手順: Ten g. of 4-chloromethyl-4-hydroxy-2-dimethylaminomethyl-2-thiazoline was dissolved in 50 ml. of 1,2-dichloroethane, and to it was added 8.6 g. of thionyl chloride dissolved in 30 ml. of 1,2-dichloroethane. The mixture was stirred at ambient temperature overnight, and then was stirred at 35° for 35 minutes and then for 1 hour at 50°. The mixture was cooled to 5° and filtered, and the solids were washed with 1,2-dichloroethane, and then were slurried in 20 ml. of methanol and 50 ml. of ethyl acetate. The crystals were then recovered by filtration and dried to obtain 6.4 g. of relatively pure product, m.p. 137°-140°. The product was identified by nmr analysis in DMSO-D6, on a 60 mHz instrument, which analysis showed characteristic features at δ3.05 (s, 6H); 4.85 (s, 2H); 4.90 (s, 2H); 7.85 (s, 1H). was stirred at 35° for 35 minutes for 1 hour at 50° The mixture was cooled to 5° filtered the solids were washed with 1,2-dichloroethane The crystals were then recovered by filtration dried to obtain 6.4 g

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

実験手順: Five g. of 4-chloromethyl-4-hydroxy-2-dimethylaminomethyl-2-thiazoline was added to 25 ml. of 1,2-dichloroethane, and 2.1 g. of sulfuryl chloride in 10 ml. of 1,2-dichloroethane was added. An exothermic reaction heated the mixture to 35° as soon as the addition began, so the mixture was cooled while the addition was made. The mixture was then stirred at ambient temperature for 1 hour, and was then heated to 42° for a short time. A 2-phase mixture formed, and the oily portion was removed and dissolved in 10 ml. of methanol. The methanol was removed under vacuum, and the residue was partially dissolved in 10 ml. of methanol, and then precipitated by addition of 25 ml. of ethyl acetate. The mixture was then cooled in the freezer, and the crystals were filtered off, washed with ethyl acetate and dried under vacuum at 30° to obtain 1.4 g. of the desired product, which was identified by nmr analysis as being substantially identical with the product of Example 5. An exothermic reaction heated the mixture to 35° as soon as the addition was cooled while the addition was then heated to 42° for a short time A 2-phase mixture formed the oily portion was removed dissolved in 10 ml The methanol was removed under vacuum the residue was partially dissolved in 10 ml of methanol, and then precipitated by addition of 25 ml The mixture was then cooled in the freezer the crystals were filtered off washed with ethyl acetate dried under vacuum at 30° to obtain 1.4 g

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

実験手順: To a flask were added 44.5 g. of dimethylaminothioacetamide, hydrochloride, 40.4 g. of 1,3-dichloropropanone, 224 ml. of 1,2-dichloroethane and 53.4 g. of sodium bicarbonate. An endothermic reaction took place and cooled the mixture to 13° on initial mixing. The mixture was then stirred overnight at ambient temperature, and the reaction was found to be essentially complete after 24 hours, by thin layer chromatography. The tlc system is silica gel, eluting with chloroform:methanol:ammonium hydroxide, 36:4:1. The mixture was then filtered, and the filter cake was washed with 1,2-dichloroethane. The filtrate was evaporated to dryness under vacuum to obtain 59.5 g. of crude product, which was washed with ethyl acetate. The washed solids were dried in air, to obtain 52.5 g. of substantially pure product, m.p. 90°-92°. To a flask were added 44.5 g An endothermic reaction cooled the mixture to 13° on initial mixing to be essentially complete after 24 hours, by thin layer chromatography eluting with chloroform The mixture was then filtered the filter cake was washed with 1,2-dichloroethane The filtrate was evaporated to dryness under vacuum to obtain 59.5 g of crude product, which was washed with ethyl acetate The washed solids were dried in air to obtain 52.5 g

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

実験手順: To a 100 ml, three necked, flask equipped with an agitator and a condensor were added 3.0 g (0.014 mol) of 2-hydroxy-2-chloromethyl-2-(dimethylaminomethyl)thiazoline (prepared as in Example 1), 50 ml of toluene and 0.95 g (0.014 mol) of sodium ethoxide. The resulting solution was stirred at room temperature for 30 minutes. A 1 ml sample of the reaction mixture was then removed from the flask and diluted according to the procedure described in Example 4. The HPLC assay set forth in Example 3 indicated that 6.6% of the thiazoline substrate had converted to the desired titled compound. To a 100 ml, three necked, flask equipped with an agitator A 1 ml sample of the reaction mixture was then removed from the flask diluted