2-异氰酰丙酸乙酯

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

实验步骤: Ethyl 2-isocyanatopropanoate (104 mg, 0.73 mmol) was added to a suspension of N-(2-aminoethyl)-4-(5-(thiophen-2-yl)thiophen-2-yl)pyrimidin-2-amine (200 mg, 0.66 mmol) in dichloromethane (10 mL) at rt and stirred for 8 h. The solid was filtered off and added to 15 mL of hydrochloric acid (5 M). After refluxing for 6 h, the mixture was cooled to rt and the precipitate was filtered off, washed with water and then dissolved in 10 mL of methanol. 50 mg of potassium carbonate was added and the mixture was stirred for 10 min. 20 mL of dichloromethane was added and the mixture was filtered through Celite. The filtrate was concentrated to give the title compound (180 mg, 68%). MS (M+H)+ 400. The solid was filtered off added to 15 mL of hydrochloric acid (5 M) After refluxing for 6 h the precipitate was filtered off washed with water dissolved in 10 mL of methanol 50 mg of potassium carbonate was added the mixture was stirred for 10 min 20 mL of dichloromethane was added the mixture was filtered through Celite The filtrate was concentrated

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

实验步骤: A mixture of 2.91 g (20 mmol) of 3-chloro-4-fluoroaniline and 3.01 g (21 mmol) of 2-isocyanato-propionic acid ethyl ester was maintained at 130°-140° C. for 91/2 hours. The resulting product was crystallized from chloroform/methanol to yield 3-(3-chloro-4-fluorophenyl)-5-methyl-hydantoin, m.p. 174°-175.5° C. was maintained at 130°-140° C. for 91/2 hours The resulting product was crystallized from chloroform/methanol

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

实验步骤: A mixture of 2.91 g (20 mmol) of 3-chloro-4-fluoroaniline and 3.01 g (21 mmol) of 2-isocyanato-propionic acid ethyl ester was maintained at 130°-140° C. for 91/2 hours. The resulting product was crystallized from chloroform/methanol to yield 3-(3-chloro-4-fluorophenyl)-5-methyl-hydantoin, m.p. 174°-175.5° C. was maintained at 130°-140° C. for 91/2 hours The resulting product was crystallized from chloroform/methanol

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

实验步骤: Ethyl 2-isocyanatopropanoate (104 mg, 0.73 mmol) was added to a suspension of N-(2-aminoethyl)-4-(5-(thiophen-2-yl)thiophen-2-yl)pyrimidin-2-amine (200 mg, 0.66 mmol) in dichloromethane (10 mL) at rt and stirred for 8 h. The solid was filtered off and added to 15 mL of hydrochloric acid (5 M). After refluxing for 6 h, the mixture was cooled to rt and the precipitate was filtered off, washed with water and then dissolved in 10 mL of methanol. 50 mg of potassium carbonate was added and the mixture was stirred for 10 min. 20 mL of dichloromethane was added and the mixture was filtered through Celite. The filtrate was concentrated to give the title compound (180 mg, 68%). MS (M+H)+ 400. The solid was filtered off added to 15 mL of hydrochloric acid (5 M) After refluxing for 6 h the precipitate was filtered off washed with water dissolved in 10 mL of methanol 50 mg of potassium carbonate was added the mixture was stirred for 10 min 20 mL of dichloromethane was added the mixture was filtered through Celite The filtrate was concentrated

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Trifluoroacetate salt of 4′-Methyl-2-(morpholin-4-ylcarbonyl)-4,5′-bi-1,3-thiazol-2′-amine, prepared as in Step II of Example 36, described above, (150 mg; 0.35 mmol; 1 eq.) is suspended in DCM (5 ml). N,N-Diisopropylethylamine (133 μl; 0.78 mmol; 2.20 eq.) is added. A solution of ethyl 2-isocyanatopropionate (Aldrich)(50.6 mg; 0.35 mmol; 1 eq.) in DCM (3 ml) is added and the resulting mixture is heated at 50° C. overnight. EtOAc is added (10 ml) and the mixture is washed with water. Organic phase is dried over MgSO4 and concentrated. The crude mixture is resubmitted to the same reaction conditions. After one night at 50° C., the conversion is complete and a similar work-up is performed. The crude product is recrystallized in MeOH, affording Compound (37) as white-off powder (92.2 mg; 58%). 1H NMR (DMSO-d6, 300 MHz) δ 1.18 (t, J=6 Hz, 3H), 2.41 (s, 3H), 2.50 (m, 2H), 3.36 (m, 2H), 3.68 (m, 6H), 4.07 (q, J=6 Hz, 2H), 4.33 (m, 2H), 6.70 (br s, 1H), 7.90 (s, 1H), 10.52 (br s, 1H). M− (ESI): 452.14; M+ (ESI): 454.11. HPLC (method A), Rt: 2.89 min (purity: 98.9%). the mixture is washed with water Organic phase is dried over MgSO4 concentrated The crude mixture is resubmitted to the same reaction conditions After one night at 50° C. The crude product is recrystallized in MeOH

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The solution of ethyl 3-isocyanatopropionate in toluene used in the above process can be prepared as follows: A mixture of 15.36 g of β-alanine ethyl ester in 600 ml of toluene is dissolved by heating to 90° C. Then 63 ml of a 20% solution of phosgene in toluene are added over 10 minutes under argon and at a temperature of 90°-95° C. Stirring at ca. 90° C. for 16 hours gives the desired solution of ethyl isocyanatopropionate, which is used direct in the above reaction. can be prepared is dissolved

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

实验步骤: Ethyl 2-isocyanatopropanoate (104 mg, 0.73 mmol) was added to a suspension of N-(2-aminoethyl)-4-(5-(thiophen-2-yl)thiophen-2-yl)pyrimidin-2-amine (200 mg, 0.66 mmol) in dichloromethane (10 mL) at rt and stirred for 8 h. The solid was filtered off and added to 15 mL of hydrochloric acid (5 M). After refluxing for 6 h, the mixture was cooled to rt and the precipitate was filtered off, washed with water and then dissolved in 10 mL of methanol. 50 mg of potassium carbonate was added and the mixture was stirred for 10 min. 20 mL of dichloromethane was added and the mixture was filtered through Celite. The filtrate was concentrated to give the title compound (180 mg, 68%). MS (M+H)+ 400. The solid was filtered off added to 15 mL of hydrochloric acid (5 M) After refluxing for 6 h the precipitate was filtered off washed with water dissolved in 10 mL of methanol 50 mg of potassium carbonate was added the mixture was stirred for 10 min 20 mL of dichloromethane was added the mixture was filtered through Celite The filtrate was concentrated

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

实验步骤: A mixture of 2.91 g (20 mmol) of 3-chloro-4-fluoroaniline and 3.01 g (21 mmol) of 2-isocyanato-propionic acid ethyl ester was maintained at 130°-140° C. for 91/2 hours. The resulting product was crystallized from chloroform/methanol to yield 3-(3-chloro-4-fluorophenyl)-5-methyl-hydantoin, m.p. 174°-175.5° C. was maintained at 130°-140° C. for 91/2 hours The resulting product was crystallized from chloroform/methanol