3-bromopentane-2,4-dione

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of morpholine-4-carbonitrile (10 g, 89.19 mmol) in EtOH (65 mL) was cooled on an ice bath. Anhydrous NH3 was bubbled through the solution for 5 min, followed by hydrogen sulfide. Soon after the introduction of H2S a white precipitate was observed. After the addition of both gases for 45 min NH3 addition was stopped and H2S continued for a further 15 minutes. The resulting precipitate was collected, washed with cold water, MeOH and dried under high vacuum to afford morpholine-4-carbothioic acid amide (12.83 g). Mp. 173-174° C. 1H-NMR (DMSO-D6) δ: 3.54 (t, 4H, J=4.9 Hz, CH2), 3.70 (m, 4H, CH2), 7.46 (brs, 2H, NH2). This was converted first to 1-(4-methyl-2-morpholin-4-yl-thiazol-5-yl)-ethanone with 3-bromo-pentane-2,4-dione, then with dimethoxymethyl-dimethyl-amine to 3-dimethylamino-1-(4-methyl-2-morpholin-4-yl-thiazol-5-yl)-propenone in the usual manner. The latter enaminone was condensed with N-(3-hydroxy-phenyl)-guanidine nitrate to afford the title compound as a. pale solid. Mp. 227-229 C. 1H-NMR (DMSO-D6) δ: 2.49 (s, 3H, CH3), 3.46 (t, 4H, J=4.4 Hz, CH2), 3.71 (t, 4H, J=4.4 Hz, pyrimidinyl-H), 6.34 (d, 1H, J=8.8 Hz, Ph-H), 6.91 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.03 (t, 1H, J=7.8 Hz, Ph-H), 7.20-7.22 (m, 2H, Ph-H), 8.34 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 9.17 (s, 1H, OH/NH), 9.32 (s, 1H, NH/OH). MS (ESI+) m/z 370.10 [M+H]+ (C18H19N5O2S requires 369.44).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of morpholine-4-carbonitrile (10 g, 89.19 mmol) in EtOH (65 mL) was cooled on an ice bath. Anhydrous NH3 was bubbled through the solution for 5 min, followed by hydrogen sulfide. Soon after the introduction of H2S a white precipitate was observed. After the addition of both gases for 45 min NH3 addition was stopped and H2S continued for a further 15 minutes. The resulting precipitate was collected, washed with cold water, MeOH and dried under high vacuum to afford morpholine-4-carbothioic acid amide (12.83 g). Mp. 173-174° C. 1H-NMR (DMSO-D6) δ: 3.54 (t, 4H, J=4.9 Hz, CH2), 3.70 (m, 4H, CH2), 7.46 (brs, 2H, NH2). This was converted first to 1-(4-methyl-2-morpholin-4-yl-thiazol-5-yl)-ethanone with 3-bromo-pentane-2,4-dione, then with dimethoxymethyl-dimethyl-amine to 3-dimethylamino-1-(4-methyl-2-morpholin-4-yl-thiazol-5-yl)-propenone in the usual manner. The latter enaminone was condensed with N-(3-hydroxy-phenyl)-guanidine nitrate to afford the title compound as a. pale solid. Mp. 227-229 C. 1H-NMR (DMSO-D6) δ: 2.49 (s, 3H, CH3), 3.46 (t, 4H, J=4.4 Hz, CH2), 3.71 (t, 4H, J=4.4 Hz, pyrimidinyl-H), 6.34 (d, 1H, J=8.8 Hz, Ph-H), 6.91 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.03 (t, 1H, J=7.8 Hz, Ph-H), 7.20-7.22 (m, 2H, Ph-H), 8.34 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 9.17 (s, 1H, OH/NH), 9.32 (s, 1H, NH/OH). MS (ESI+) m/z 370.10 [M+H]+ (C18H19N5O2S requires 369.44).

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Bromo-2,4-pentandione (P8) (26.66 g, 148.93 mmol) obtained in Step I as described above, is dissolved in acetone (87 mL). This mixture is added to a solution of urea (22.36 g, 372 mmol, 2.5 eq) in water (20 mL). The resulting mixture is heated in order to obtain a clear solution and is distributed into 38 microwave tubes (3 ml each). The vials are heated to 100° C. for 1200 s each in the microwave oven. All vials are combined, NaHCO3 sat (100 ml) and EtOAc (100 ml) are added, the aqueous phase is saturated with NaCl and the phases are separated. The aqueous phase is extracted with EtOAc (4 times 100 ml). Combined organic layers are dried over MgSO4, filtrated and evaporated under reduced pressure to give 1-(2-amino-4-methyl-1,3-oxazol-5-yl)ethanone (P5) as an orange solid (12.09 g). It is further recrystallized in MeOH, affording a brownish solid (5.56 g, 27%). 1H NMR (DMSO-d) δ: 2.22 (s, 3H), 2.25 (s, 3H), 7.51 (s, 2H). The resulting mixture is heated in order to obtain a clear solution are added the phases are separated The aqueous phase is extracted with EtOAc (4 times 100 ml) Combined organic layers are dried over MgSO4 filtrated evaporated under reduced pressure

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Bromo-2,4-pentandione (P8) (26.66 g, 148.93 mmol) obtained in Step I as described above, is dissolved in acetone (87 mL). This mixture is added to a solution of urea (22.36 g, 372 mmol, 2.5 eq) in water (20 mL). The resulting mixture is heated in order to obtain a clear solution and is distributed into 38 microwave tubes (3 ml each). The vials are heated to 100° C. for 1200 s each in the microwave oven. All vials are combined, NaHCO3 sat (100 ml) and EtOAc (100 ml) are added, the aqueous phase is saturated with NaCl and the phases are separated. The aqueous phase is extracted with EtOAc (4 times 100 ml). Combined organic layers are dried over MgSO4, filtrated and evaporated under reduced pressure to give 1-(2-amino-4-methyl-1,3-oxazol-5-yl)ethanone (P5) as an orange solid (12.09 g). It is further recrystallized in MeOH, affording a brownish solid (5.56 g, 27%). 1H NMR (DMSO-d) δ: 2.22 (s, 3H), 2.25 (s, 3H), 7.51 (s, 2H). The resulting mixture is heated in order to obtain a clear solution are added the phases are separated The aqueous phase is extracted with EtOAc (4 times 100 ml) Combined organic layers are dried over MgSO4 filtrated evaporated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of morpholine-4-carbonitrile (10 g, 89.19 mmol) in EtOH (65 mL) was cooled on an ice bath. Anhydrous NH3 was bubbled through the solution for 5 min, followed by hydrogen sulfide. Soon after the introduction of H2S a white precipitate was observed. After the addition of both gases for 45 min NH3 addition was stopped and H2S continued for a further 15 minutes. The resulting precipitate was collected, washed with cold water, MeOH and dried under high vacuum to afford morpholine-4-carbothioic acid amide (12.83 g). Mp. 173-174° C. 1H-NMR (DMSO-D6) δ: 3.54 (t, 4H, J=4.9 Hz, CH2), 3.70 (m, 4H, CH2), 7.46 (brs, 2H, NH2). This was converted first to 1-(4-methyl-2-morpholin-4-yl-thiazol-5-yl)-ethanone with 3-bromo-pentane-2,4-dione, then with dimethoxymethyl-dimethyl-amine to 3-dimethylamino-1-(4-methyl-2-morpholin-4-yl-thiazol-5-yl)-propenone in the usual manner. The latter enaminone was condensed with N-(3-hydroxy-phenyl)-guanidine nitrate to afford the title compound as a pale solid. Mp. 227-229 C. 1H-NMR (DMSO-D6) δ: 2.49 (s, 3H, CH3), 3.46 (t, 4H, J=4.4 Hz, CH2), 3.71 (t, 4H, J=4.4 Hz, pyrimidinyl-H), 6.34 (d, 1H, J=8.8 Hz, Ph-H), 6.91 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.03 (t, 1H, J=7.8 Hz, Ph-H), 7.20-7.22 (m, 2H, Ph-H), 8.34 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 9.17 (s, 1H, OH/NH), 9.32 (s, 1H, NH/OH). MS (ESI+) m/z 370.10 [M+H]+ (C18H19N5O2S requires 369.44).

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Bromo-2,4-pentandione (P8) (26.66 g, 148.93 mmol) obtained in Step I as described above, is dissolved in acetone (87 mL). This mixture is added to a solution of urea (22.36 g, 372 mmol, 2.5 eq) in water (20 mL). The resulting mixture is heated in order to obtain a clear solution and is distributed into 38 microwave tubes (3 ml each). The vials are heated to 100° C. for 1200 s each in the microwave oven. All vials are combined, NaHCO3 sat (100 ml) and EtOAc (100 ml) are added, the aqueous phase is saturated with NaCl and the phases are separated. The aqueous phase is extracted with EtOAc (4 times 100 ml). Combined organic layers are dried over MgSO4, filtrated and evaporated under reduced pressure to give 1-(2-amino-4-methyl-1,3-oxazol-5-yl)ethanone (P5) as an orange solid (12.09 g). It is further recrystallized in MeOH, affording a brownish solid (5.56 g, 27%). 1H NMR (DMSO-d6) δ: 2.22 (s, 3H), 2.25 (s, 3H), 7.51 (s, 2H). The resulting mixture is heated in order to obtain a clear solution are added the phases are separated The aqueous phase is extracted with EtOAc (4 times 100 ml) Combined organic layers are dried over MgSO4 filtrated evaporated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of morpholine-4-carbonitrile (10 g, 89.19 mmol) in EtOH (65 mL) was cooled on an ice bath. Anhydrous NH3 was bubbled through the solution for 5 min, followed by hydrogen sulfide. Soon after the introduction of H2S a white precipitate was observed. After the addition of both gases for 45 min NH3 addition was stopped and H2S continued for a further 15 minutes. The resulting precipitate was collected, washed with cold water, MeOH and dried under high vacuum to afford morpholine-4-carbothioic acid amide (12.83 g). Mp. 173-174° C. 1H-NMR (DMSO-D6) δ: 3.54 (t, 4H, J=4.9 Hz, CH2), 3.70 (m, 4H, CH2), 7.46 (brs, 2H, NH2). This was converted first to 1-(4-methyl-2-morpholin-4-yl-thiazol-5-yl)-ethanone with 3-bromo-pentane-2,4-dione, then with dimethoxymethyl-dimethyl-amine to 3-dimethylamino-1-(4-methyl-2-morpholin-4-yl-thiazol-5-yl)-propenone in the usual manner. The latter enaminone was condensed with N-(3-hydroxy-phenyl)-guanidine nitrate to afford the title compound as a. pale solid. Mp. 227-229 C. 1H-NMR (DMSO-D6) δ: 2.49 (s, 3H, CH3), 3.46 (t, 4H, J=4.4 Hz, CH2), 3.71 (t, 4H, J=4.4 Hz, pyrimidinyl-H), 6.34 (d, 1H, J=8.8 Hz, Ph-H), 6.91 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.03 (t, 1H, J=7.8 Hz, Ph-H), 7.20-7.22 (m, 2H, Ph-H), 8.34 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 9.17 (s, 1H, OH/NH), 9.32 (s, 1H, NH/OH). MS (ESI+) m/z 370.10 [M+H]+ (C18H19N5O2S requires 369.44).