2-(4-fluorophenyl)acetohydrazide

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3-(benzyloxy)-N,9,9-trimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbothioamide (0.1 g, 0.278 mmol, 1.0 equiv) in acetonitrile (0.9 mL) under a nitrogen atmosphere, was added MeI (0.070 mL, 1.11 mmol, 4 equiv). The reaction was heated at 50° C. (oil bath) for 45 min. The reaction was then cooled to ambient temperature and concentrated in vacuo. 2-(4-Fluorophenyl)acetohydrazide (0.14 g, 0.84 mmol, 3 equiv) was then added to the residue followed by DMF (2 mL) and the slurry was heated at 140° C. (oil bath). After stirring 16 h, the reaction was cooled to ambient temperature and concentrated in vacuo. The residue was added to a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×3). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo. The crude product was treated with DMF (˜1.5 mL). After trying to dissolve material, the insoluble portion was filtered and washed with methanol to provide the title compound (0.024 g, 22% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.21 (dd, J=8.81, 5.29 Hz, 2H), 7.03 (t, J=8.69 Hz, 2H), 4.24 (s, 2H), 4.04 (q, J=2.77 Hz, 4H), 3.93 (s, 3H), 1.57 (s, 6H); LCMS (ES+, (M+H)+) m/z 386.22. The reaction was then cooled to ambient temperature concentrated in vacuo the slurry was heated at 140° C. (oil bath) the reaction was cooled to ambient temperature concentrated in vacuo The residue was added to a saturated aqueous solution of NaHCO3 extracted with CH2Cl2 (×3) The combined CH2Cl2 extracts were dried (Na2SO4) concentrated in vacuo The crude product was treated with DMF (˜1.5 mL) to dissolve material the insoluble portion was filtered washed with methanol

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a slurry of 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbothioamide (0.04 g, 0.116 mmol, 1.0 equiv) in acetonitrile (1.2 mL) under a nitrogen atmosphere, was added MeI (0.011 mL, 0.174 mmol, 1.5 equiv). The reaction was heated at 50° C. (oil bath) for 1 h. The reaction was then cooled to ambient temperature and concentrated in vacuo. 2-(4-Fluorophenyl)acetohydrazide (0.058 g, 0.35 mmol, 3 equiv) was then added to the residue followed by methanol (1 mL) and the slurry was heated at 70° C. (oil bath). After stirring 1 h, the reaction was cooled to ambient temperature and concentrated in vacuo. DMF (1 mL) was added to the residue and the solution was heated at 150° C. (oil bath) for 3.5 h. The reaction was then cooled to ambient temperature and stirred 3 d. The reaction was heated at 140° C. (oil bath) for 2 h. The reaction was cooled to ambient temperature and concentrated in vacuo. The residue was added to a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×2). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo. The crude product was purified by reverse phase preparatory HPLC to provide the title compound (0.021 g, 49% yield) as a gray solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.99 (s, 2H), 7.21-7.39 (m, 2H), 7.00 (t, J=8.69 Hz, 2H), 4.17 (s, 2H), 4.05 (s, 4H), 1.62 (s, 6H); LCMS (ES+, (M+H)+) m/z 372.16. The reaction was then cooled to ambient temperature concentrated in vacuo the slurry was heated at 70° C. (oil bath) the reaction was cooled to ambient temperature concentrated in vacuo DMF (1 mL) was added to the residue the solution was heated at 150° C. (oil bath) for 3.5 h The reaction was then cooled to ambient temperature stirred 3 d The reaction was heated at 140° C. (oil bath) for 2 h The reaction was cooled to ambient temperature concentrated in vacuo The residue was added to a saturated aqueous solution of NaHCO3 extracted with CH2Cl2 (×2) The combined CH2Cl2 extracts were dried (Na2SO4) concentrated in vacuo The crude product was purified by reverse phase preparatory HPLC

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

実験手順: To a solution of hydrazine (0.46 mL, 14.49 mmol, 2.5 equiv) in CH2Cl2 (29 mL) was added slowly over 30 sec 2-(4-fluorophenyl)acetyl chloride (0.79 mL, 5.79 mmol, 1.0 equiv). Slight warming of the mixture and white precipitate were observed. After stirring 45 min, the mixture was poured into a saturated aqueous solution of NaHCO3, layered with CH2Cl2 forming a thick emulsion. This emulsion was filtered through a medium glass frit to give a biphasic homogenous solution. This was extracted with CH2Cl2 (×3). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo to provide the title compound (1.22 g, 124% yield) as a white solid. Source of extra mass is unclear as product is of high purity. Extra mass may reflect a measuring error of the acid chloride. 1H NMR (400 MHz, CDCl3) δ ppm 7.19-7.24 (m, 2H), 6.99-7.07 (m, 2H), 6.60 (s, 1H), 3.85 (d, J=2.01 Hz, 2H), 3.52 (s, 2H); LCMS (ES+, (M+H)+) m/z 169.22. Slight warming of the mixture and white precipitate This emulsion was filtered through a medium glass frit to give a biphasic homogenous solution This was extracted with CH2Cl2 (×3) The combined CH2Cl2 extracts were dried (Na2SO4) concentrated in vacuo

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3-(benzyloxy)-N,9,9-trimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbothioamide (0.1 g, 0.278 mmol, 1.0 equiv) in acetonitrile (0.9 mL) under a nitrogen atmosphere, was added MeI (0.070 mL, 1.11 mmol, 4 equiv). The reaction was heated at 50° C. (oil bath) for 45 min. The reaction was then cooled to ambient temperature and concentrated in vacuo. 2-(4-Fluorophenyl)acetohydrazide (0.14 g, 0.84 mmol, 3 equiv) was then added to the residue followed by DMF (2 mL) and the slurry was heated at 140° C. (oil bath). After stirring 16 h, the reaction was cooled to ambient temperature and concentrated in vacuo. The residue was added to a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×3). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo. The crude product was treated with DMF (˜1.5 mL). After trying to dissolve material, the insoluble portion was filtered and washed with methanol to provide the title compound (0.024 g, 22% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.21 (dd, J=8.81, 5.29 Hz, 2H), 7.03 (t, J=8.69 Hz, 2H), 4.24 (s, 2H), 4.04 (q, J=2.77 Hz, 4H), 3.93 (s, 3H), 1.57 (s, 6H); LCMS (ES+, (M+H)+) m/z 386.22. The reaction was then cooled to ambient temperature concentrated in vacuo the slurry was heated at 140° C. (oil bath) the reaction was cooled to ambient temperature concentrated in vacuo The residue was added to a saturated aqueous solution of NaHCO3 extracted with CH2Cl2 (×3) The combined CH2Cl2 extracts were dried (Na2SO4) concentrated in vacuo The crude product was treated with DMF (˜1.5 mL) to dissolve material the insoluble portion was filtered washed with methanol

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a slurry of 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbothioamide (0.04 g, 0.116 mmol, 1.0 equiv) in acetonitrile (1.2 mL) under a nitrogen atmosphere, was added MeI (0.011 mL, 0.174 mmol, 1.5 equiv). The reaction was heated at 50° C. (oil bath) for 1 h. The reaction was then cooled to ambient temperature and concentrated in vacuo. 2-(4-Fluorophenyl)acetohydrazide (0.058 g, 0.35 mmol, 3 equiv) was then added to the residue followed by methanol (1 mL) and the slurry was heated at 70° C. (oil bath). After stirring 1 h, the reaction was cooled to ambient temperature and concentrated in vacuo. DMF (1 mL) was added to the residue and the solution was heated at 150° C. (oil bath) for 3.5 h. The reaction was then cooled to ambient temperature and stirred 3 d. The reaction was heated at 140° C. (oil bath) for 2 h. The reaction was cooled to ambient temperature and concentrated in vacuo. The residue was added to a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×2). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo. The crude product was purified by reverse phase preparatory HPLC to provide the title compound (0.021 g, 49% yield) as a gray solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.99 (s, 2H), 7.21-7.39 (m, 2H), 7.00 (t, J=8.69 Hz, 2H), 4.17 (s, 2H), 4.05 (s, 4H), 1.62 (s, 6H); LCMS (ES+, (M+H)+) m/z 372.16. The reaction was then cooled to ambient temperature concentrated in vacuo the slurry was heated at 70° C. (oil bath) the reaction was cooled to ambient temperature concentrated in vacuo DMF (1 mL) was added to the residue the solution was heated at 150° C. (oil bath) for 3.5 h The reaction was then cooled to ambient temperature stirred 3 d The reaction was heated at 140° C. (oil bath) for 2 h The reaction was cooled to ambient temperature concentrated in vacuo The residue was added to a saturated aqueous solution of NaHCO3 extracted with CH2Cl2 (×2) The combined CH2Cl2 extracts were dried (Na2SO4) concentrated in vacuo The crude product was purified by reverse phase preparatory HPLC

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

実験手順: To a solution of hydrazine (0.46 mL, 14.49 mmol, 2.5 equiv) in CH2Cl2 (29 mL) was added slowly over 30 sec 2-(4-fluorophenyl)acetyl chloride (0.79 mL, 5.79 mmol, 1.0 equiv). Slight warming of the mixture and white precipitate were observed. After stirring 45 min, the mixture was poured into a saturated aqueous solution of NaHCO3, layered with CH2Cl2 forming a thick emulsion. This emulsion was filtered through a medium glass frit to give a biphasic homogenous solution. This was extracted with CH2Cl2 (×3). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo to provide the title compound (1.22 g, 124% yield) as a white solid. Source of extra mass is unclear as product is of high purity. Extra mass may reflect a measuring error of the acid chloride. 1H NMR (400 MHz, CDCl3) δ ppm 7.19-7.24 (m, 2H), 6.99-7.07 (m, 2H), 6.60 (s, 1H), 3.85 (d, J=2.01 Hz, 2H), 3.52 (s, 2H); LCMS (ES+, (M+H)+) m/z 169.22. Slight warming of the mixture and white precipitate This emulsion was filtered through a medium glass frit to give a biphasic homogenous solution This was extracted with CH2Cl2 (×3) The combined CH2Cl2 extracts were dried (Na2SO4) concentrated in vacuo

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

実験手順: To a solution of hydrazine (0.46 mL, 14.49 mmol, 2.5 equiv) in CH2Cl2 (29 mL) was added slowly over 30 sec 2-(4-fluorophenyl)acetyl chloride (0.79 mL, 5.79 mmol, 1.0 equiv). Slight warming of the mixture and white precipitate were observed. After stirring 45 min, the mixture was poured into a saturated aqueous solution of NaHCO3, layered with CH2Cl2 forming a thick emulsion. This emulsion was filtered through a medium glass frit to give a biphasic homogenous solution. This was extracted with CH2Cl2 (×3). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo to provide the title compound (1.22 g, 124% yield) as a white solid. Source of extra mass is unclear as product is of high purity. Extra mass may reflect a measuring error of the acid chloride. 1H NMR (400 MHz, CDCl3) δ ppm 7.19-7.24 (m, 2H), 6.99-7.07 (m, 2H), 6.60 (s, 1H), 3.85 (d, J=2.01 Hz, 2H), 3.52 (s, 2H); LCMS (ES+, (M+H)+) m/z 169.22. Slight warming of the mixture and white precipitate This emulsion was filtered through a medium glass frit to give a biphasic homogenous solution This was extracted with CH2Cl2 (×3) The combined CH2Cl2 extracts were dried (Na2SO4) concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: The title compound was prepared as described in Example 17 from 4-fluorophenylacetic acid hydrazide (1.04 mmol) and 3-chloro-6-thiophen-2-yl-pyridazine (0.52 mmol) as a pale beige solid. 1H NMR (CD3OD) δ 8.19 (1H, d, J=9.9 Hz), 7.93 (1H, dd, J=3.8 Hz, 0.9 Hz), 7.90 (1H, d, J=9.9 Hz), 7.75 (1H, dd, J=5.0 Hz, 1.0 Hz), 7.50 (2H, dd, J=9.0 Hz, 5.3 Hz), 7.24 (1H, dd, J=5.3 Hz, 3.8 Hz), 7.06 (2H, t, J=8.8 Hz), 4.59 (2H, s). ESI-MS (m/z): Calcd for C16H11FN4S: 310.1; found 311.2 (M+H).

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

実験手順: The title compound was prepared in analogy to example 71c) starting with [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (200 mg, 0.76 mmol) and (4-fluoro-phenyl)-acetic acid hydrazide (141 mg, 0.76 mmol). Obtained as a greyish solid (21 mg, 7%).

反応条件: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Solid BrCN 13.37 g (130 mmol, 1.1 eq.) was added in one portion into ice-cooled slurry of (4-Fluoro-phenyl)-acetic acid hydrazide (19.85 g, 118 mmol) and KHCO3 14.77 g (147.5 mmol, 1.25 eq.) in MeOH (150 mL) in a 1L flask. (Followed by MeOH 10 mL to wash the funnel). The mixture was stirred on ice bath at 0-5° C. for 2 hours in a loose-capped flask, then the bath allowed to melt gradually and then the mixture was stirred at 5 to 20° C. overnight (17 hrs). The reaction mixture was diluted with water (200 mL), stirred for 1 hour in an open flask, then cooled on ice bath. The precipitate was collected by filtration, washed with water and dried on highvac. [1st fraction]The supernatants were concentrated on rotavap form warm (40° C.) water bath to remove all MeOH and some water. The obtained slurry was cooled to room temperature, the precipitate was collected by filtration, washed with water and dried on highvac. [2nd fraction]. Combined yield: 20.836 g (91.5%) of a white crystalline solid. to wash the funnel) the mixture was stirred at 5 to 20° C. overnight (17 hrs) The reaction mixture was diluted with water (200 mL) stirred for 1 hour in an open flask cooled on ice bath The precipitate was collected by filtration washed with water dried on highvac [1st fraction]The supernatants were concentrated on rotavap form warm (40° C.) water bath to remove all MeOH The obtained slurry was cooled to room temperature the precipitate was collected by filtration washed with water dried on highvac