4-氯-4-(2,2,2-三氯乙基)氧杂环丁烷-2-one

反应条件: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Two separate solutions of 1 (62.5 g, 0.26 mmol) and morpholine (24.0 g, 0.28 mol) in DCM (120 ml) were added simultaneously to a mixture of NaHCO3 (44.0 g, 0.52 mol) in dry DCM (300 ml). The reaction was maintained at 15° C. over 140 minutes with stirring. The reaction was filtered, washed with DCM (3×100 ml) and the combined organic layers were concentrated in vacuo to a slurry which was then passed through a short silica pad, and further washed with DCM (4×100 ml). The combined organic layers were concentrated in vacuo, suspended in hexane (400 ml) and stirred for 1 hour, filtered and dried to give a cream solid. The solid was suspended in TBME (100 ml), stirred for 15 minutes, filtered, washed with TBME and dried to give 2 as a white powder (47.8 g, 72%). m/z (LC-MS, ESP): 252 (M++1). The reaction was filtered washed with DCM (3×100 ml) the combined organic layers were concentrated in vacuo to a slurry which further washed with DCM (4×100 ml) The combined organic layers were concentrated in vacuo stirred for 1 hour filtered dried to give a cream solid stirred for 15 minutes filtered washed with TBME dried

反应条件: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Two separate solutions of 1 (62.5 g, 0.26 mmol) and morpholine (24.0 g, 0.28 mol) in DCM (120 ml) were added simultaneously to a mixture of NaHCO3 (44.0 g, 0.52 mol) in dry DCM (300 ml). The reaction was maintained at 15° C. over 140 minutes with stirring. The reaction was filtered, washed with DCM (3×100 ml) and the combined organic layers were concentrated in vacuo to a slurry which was then passed through a short silica pad, and further washed with DCM (4×100 ml). The combined organic layers were concentrated in vacuo, suspended in hexane (400 ml) and stirred for 1 hour, filtered and dried to give a cream solid. The solid was suspended in TBME (100 ml), stirred for 15 minutes, filtered, washed with TBME and dried to give 2 as a white powder (47.8 g, 72%). m/z (LC-MS, ESP): 252 (M++1). The reaction was filtered washed with DCM (3×100 ml) the combined organic layers were concentrated in vacuo to a slurry which further washed with DCM (4×100 ml) The combined organic layers were concentrated in vacuo stirred for 1 hour filtered dried to give a cream solid stirred for 15 minutes filtered washed with TBME dried

反应条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 119 Parts of 4-chloro-4-(2,2,2-trichloroethyl)-oxetan-2-one and 95.5 parts of guanidine hydrochloride were charged to a reaction flask and heated in an oil bath at 140° C. for 15 minutes. The solid dissolved and HCl gas was evolved. The oil bath temperature was raised to 160° C. and heating was continued for a further 45 minutes. The heat was removed and the reaction mass was stirred until cool and solidified. The solid was stirred with 250 parts of ethyl acetate and filtered. The filtrate was discarded and the solid dissolved in 1000 parts of hot water, treated with charcoal and filtered. The aqueous solution was cooled and neutralised by the addition of saturated sodium acetate solution. The precipitated solid was filtered and washed with water. This crude product was then dissolved in 550 parts of concentrated hydrochloric acid, diluted with 800 parts of water and stirred with 5 parts of charcoal for 20 minutes. The solution was filtered and the product precipitated by the addition of saturated sodium acetate solution to pH 6. The solid was filtered, washed with water and dried in a vacuum oven at 110° C. to give 2-amino-4-(2,2-dichloro-vinyl)-6-hydroxypyrimidine m.p. 245°-248° C. (decomposition). The solid dissolved The oil bath temperature was raised to 160° C. heating The heat was removed until cool The solid was stirred with 250 parts of ethyl acetate filtered the solid dissolved in 1000 parts of hot water treated with charcoal filtered The aqueous solution was cooled neutralised by the addition of saturated sodium acetate solution The precipitated solid was filtered washed with water This crude product was then dissolved in 550 parts of concentrated hydrochloric acid diluted with 800 parts of water stirred with 5 parts of charcoal for 20 minutes The solution was filtered the product precipitated by the addition of saturated sodium acetate solution to pH 6 The solid was filtered washed with water dried in a vacuum oven at 110° C.

反应条件: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Two separate solutions of 1 (62.5 g, 0.26 mmol) and morpholine (24.0 g, 0.28 mol) in DCM (120 ml) were added simultaneously to a mixture of NaHCO3 (44.0 g, 0.52 mol) in dry DCM (300 ml). The reaction was maintained at 15° C. over 140 minutes with stirring. The reaction was filtered, washed with DCM (3×100 ml) and the combined organic layers were concentrated in vacuo to a slurry which was then passed through a short silica pad, and further washed with DCM (4×100 ml). The combined organic layers were concentrated in vacuo, suspended in hexane (400 ml) and stirred for 1 hour, filtered and dried to give a cream solid. The solid was suspended in TBME (100 ml), stirred for 15 minutes, filtered, washed with TBME and dried to give 2 as a white powder (47.8 g, 72%). m/z (LC-MS, ESP): 252 (M++1). The reaction was filtered washed with DCM (3×100 ml) the combined organic layers were concentrated in vacuo to a slurry which further washed with DCM (4×100 ml) The combined organic layers were concentrated in vacuo stirred for 1 hour filtered dried to give a cream solid stirred for 15 minutes filtered washed with TBME dried

反应条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 119 Parts of 4-chloro-4-(2,2,2-trichloroethyl)-oxetan-2-one and 95.5 parts of guanidine hydrochloride were charged to a reaction flask and heated in an oil bath at 140° C. for 15 minutes. The solid dissolved and HCl gas was evolved. The oil bath temperature was raised to 160° C. and heating was continued for a further 45 minutes. The heat was removed and the reaction mass was stirred until cool and solidified. The solid was stirred with 250 parts of ethyl acetate and filtered. The filtrate was discarded and the solid dissolved in 1000 parts of hot water, treated with charcoal and filtered. The aqueous solution was cooled and neutralised by the addition of saturated sodium acetate solution. The precipitated solid was filtered and washed with water. This crude product was then dissolved in 550 parts of concentrated hydrochloric acid, diluted with 800 parts of water and stirred with 5 parts of charcoal for 20 minutes. The solution was filtered and the product precipitated by the addition of saturated sodium acetate solution to pH 6. The solid was filtered, washed with water and dried in a vacuum oven at 110° C. to give 2-amino-4-(2,2-dichloro-vinyl)-6-hydroxypyrimidine m.p. 245°-248° C. (decomposition). The solid dissolved The oil bath temperature was raised to 160° C. heating The heat was removed until cool The solid was stirred with 250 parts of ethyl acetate filtered the solid dissolved in 1000 parts of hot water treated with charcoal filtered The aqueous solution was cooled neutralised by the addition of saturated sodium acetate solution The precipitated solid was filtered washed with water This crude product was then dissolved in 550 parts of concentrated hydrochloric acid diluted with 800 parts of water stirred with 5 parts of charcoal for 20 minutes The solution was filtered the product precipitated by the addition of saturated sodium acetate solution to pH 6 The solid was filtered washed with water dried in a vacuum oven at 110° C.

反应条件: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Two separate solutions of 4-Chloro-4-(2,2,2-trichloro-ethyl)-oxetan-2-one (62.5 g, 0.26 mmol) and morpholine (24.0 g, 0.28 mol) in dichloromethane (120 ml) were added simultaneously to a mixture of NaHCO3 (44.0 g, 0.52 mol) in dry dichloromethane (300 ml). The reaction was maintained at 15° C. over 140 min with stirring. The reaction was filtered, washed with dichloromethane (3×100 ml) and the combined organic layers were concentrated in vacuo to a slurry which was then passed through a short silica pad, and further washed with dichloromethane (4×100 ml). The combined organic layers were concentrated in vacuo, suspended in hexane (400 ml) and stirred for 1 h, filtered and dried to give a cream solid. The solid was suspended in tert-butyl methyl ether (100 ml), stirred for 15 min, filtered, washed with butyl methyl ether and dried to give the desired compound as a white powder (47.8 g, 72%). m/z (LC-MS, ESP): 252 (M++1). The reaction was filtered washed with dichloromethane (3×100 ml) the combined organic layers were concentrated in vacuo to a slurry which further washed with dichloromethane (4×100 ml) The combined organic layers were concentrated in vacuo stirred for 1 h filtered dried to give a cream solid stirred for 15 min filtered washed with butyl methyl ether dried

反应条件: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Two separate solutions of 4-Chloro-4-(2,2,2-trichloro-ethyl)-oxetan-2-one (62.5 g, 0.26 mmol) and morpholine (24.0 g, 0.28 mol) in dichloromethane (120 ml) were added simultaneously to a mixture of NaHCO3 (44.0 g, 0.52 mol) in dry dichloromethane (300 ml). The reaction was maintained at 15° C. over 140 min with stirring. The reaction was filtered, washed with dichloromethane (3×100 ml) and the combined organic layers were concentrated in vacuo to a slurry which was then passed through a short silica pad, and further washed with dichloromethane (4×100 ml). The combined organic layers were concentrated in vacuo, suspended in hexane (400 ml) and stirred for 1 h, filtered and dried to give a cream solid. The solid was suspended in tert-butyl methyl ether (100 ml), stirred for 15 min, filtered, washed with butyl methyl ether and dried to give the desired compound as a white powder (47.8 g, 72%). m/z (LC-MS, ESP): 252 (M++1). The reaction was filtered washed with dichloromethane (3×100 ml) the combined organic layers were concentrated in vacuo to a slurry which further washed with dichloromethane (4×100 ml) The combined organic layers were concentrated in vacuo stirred for 1 h filtered dried to give a cream solid stirred for 15 min filtered washed with butyl methyl ether dried

反应条件: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Two separate solutions of 4-Chloro-4-(2,2,2-trichloro-ethyl)-oxetan-2-one (62.5 g, 0.26 mmol) and morpholine (24.0 g, 0.28 mol) in dichloromethane (120 ml) were added simultaneously to a mixture of NaHCO3 (44.0 g, 0.52 mol) in dry dichloromethane (300 ml). The reaction was maintained at 15° C. over 140 min with stirring. The reaction was filtered, washed with dichloromethane (3×100 ml) and the combined organic layers were concentrated in vacuo to a slurry which was then passed through a short silica pad, and further washed with dichloromethane (4×100 ml). The combined organic layers were concentrated in vacuo, suspended in hexane (400 ml) and stirred for 1 h, filtered and dried to give a cream solid. The solid was suspended in tert-butyl methyl ether (100 ml), stirred for 15 min, filtered, washed with butyl methyl ether and dried to give the desired compound as a white powder (47.8 g, 72%). m/z (LC-MS, ESP): 252 (M++1). The reaction was filtered washed with dichloromethane (3×100 ml) the combined organic layers were concentrated in vacuo to a slurry which further washed with dichloromethane (4×100 ml) The combined organic layers were concentrated in vacuo stirred for 1 h filtered dried to give a cream solid stirred for 15 min filtered washed with butyl methyl ether dried

反应条件: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Two separate solutions of 1 (62.5 g, 0.26 mmol) and morpholine (24.0 g, 0.28 mol) in DCM (120 ml) were added simultaneously to a mixture of NaHCO3 (44.0 g, 0.52 mol) in dry DCM (300 ml). The reaction was maintained at 15° C. over 140 minutes with stirring. The reaction was filtered, washed with DCM (3×100 ml) and the combined organic layers were concentrated in vacuo to a slurry which was then passed through a short silica pad, and further washed with DCM (4×100 ml). The combined organic layers were concentrated in vacuo, suspended in hexane (400 ml) and stirred for 1 hour, filtered and dried to give a cream solid. The solid was suspended in TBME (100 ml), stirred for 15 minutes, filtered, washed with TBME and dried to give 2 as a white powder (47.8 g, 72%). m/z (LC-MS, ESP): 252 (M++1). The reaction was filtered washed with DCM (3×100 ml) the combined organic layers were concentrated in vacuo to a slurry which further washed with DCM (4×100 ml) The combined organic layers were concentrated in vacuo stirred for 1 hour filtered dried to give a cream solid stirred for 15 minutes filtered washed with TBME dried

反应条件: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Two separate solutions of 4-Chloro-4-(2,2,2-trichloro-ethyl)-oxetan-2-one (62.5 g, 0.26 mmol) and morpholine (24.0 g, 0.28 mol) in dichloromethane (120 ml) were added simultaneously to a mixture of NaHCO3 (44.0 g, 0.52 mol) in dry dichloromethane (300 ml). The reaction was maintained at 15° C. over 140 min with stirring. The reaction was filtered, washed with dichloromethane (3×100 ml) and the combined organic layers were concentrated in vacuo to a slurry which was then passed through a short silica pad, and further washed with dichloromethane (4×100 ml). The combined organic layers were concentrated in vacuo, suspended in hexane (400 ml) and stirred for 1 h, filtered and dried to give a cream solid. The solid was suspended in tert-butyl methyl ether (100 ml), stirred for 15 min, filtered, washed with butyl methyl ether and dried to give the desired compound as a white powder (47.8 g, 72%). m/z (LC-MS, ESP): 252 (M++1). The reaction was filtered washed with dichloromethane (3×100 ml) the combined organic layers were concentrated in vacuo to a slurry which further washed with dichloromethane (4×100 ml) The combined organic layers were concentrated in vacuo stirred for 1 h filtered dried to give a cream solid stirred for 15 min filtered washed with butyl methyl ether dried

反应条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 119 Parts of 4-chloro-4-(2,2,2-trichloroethyl)-oxetan-2-one and 95.5 parts of guanidine hydrochloride were charged to a reaction flask and heated in an oil bath at 140° C. for 15 minutes. The solid dissolved and HCl gas was evolved. The oil bath temperature was raised to 160° C. and heating was continued for a further 45 minutes. The heat was removed and the reaction mass was stirred until cool and solidified. The solid was stirred with 250 parts of ethyl acetate and filtered. The filtrate was discarded and the solid dissolved in 1000 parts of hot water, treated with charcoal and filtered. The aqueous solution was cooled and neutralised by the addition of saturated sodium acetate solution. The precipitated solid was filtered and washed with water. This crude product was then dissolved in 550 parts of concentrated hydrochloric acid, diluted with 800 parts of water and stirred with 5 parts of charcoal for 20 minutes. The solution was filtered and the product precipitated by the addition of saturated sodium acetate solution to pH 6. The solid was filtered, washed with water and dried in a vacuum oven at 110° C. to give 2-amino-4-(2,2-dichloro-vinyl)-6-hydroxypyrimidine m.p. 245°-248° C. (decomposition). The solid dissolved The oil bath temperature was raised to 160° C. heating The heat was removed until cool The solid was stirred with 250 parts of ethyl acetate filtered the solid dissolved in 1000 parts of hot water treated with charcoal filtered The aqueous solution was cooled neutralised by the addition of saturated sodium acetate solution The precipitated solid was filtered washed with water This crude product was then dissolved in 550 parts of concentrated hydrochloric acid diluted with 800 parts of water stirred with 5 parts of charcoal for 20 minutes The solution was filtered the product precipitated by the addition of saturated sodium acetate solution to pH 6 The solid was filtered washed with water dried in a vacuum oven at 110° C.