ethylurea

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

Procedure: By the procedures of Example 4, 5.3 g (60 mmol) of ethyl urea was reacted with 10.9 g (50 mmol) of ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 140°-150° C. for 24 hours. The product mixture was treated with methylene chloride, washed with water, dried and concentrated. The residue was recrystallized from methylcyclohexane to yield 8.0 g of crystal product (m.p.=89°-90° C.) identified in Table I. washed with water dried concentrated The residue was recrystallized from methylcyclohexane

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

Procedure: Acetylacetone (9.0 g., 0.09 moles) and ethylurea (7.13 g., 0.081 moles) are dissolved in 30 ml. ethanol. The solution is cooled in an ice-water bath while 30 g. of cold concentrated sulfuric acid is added. The resulting yellow solution is stored at room temperature for 10 days and diluted with a large volume of ether. The ether-ethanol mixture is decanted from the thick syrupy residue which is washed with additional fresh ether. The residue is made basic with 2.5 N sodium hydroxide and extracted throughly with methylene chloride. The organic extracts are dried over sodium sulfate, treated with charcoal, filtered, and evaporated under vacuum affording 1-ethyl-4,6-dimethyl-2(1H)-pyrimidinone as a tan solid (7.6 g., 62%). The solution is cooled in an ice-water bath while 30 g The ether-ethanol mixture is decanted from the thick syrupy residue which is washed with additional fresh ether extracted throughly with methylene chloride The organic extracts are dried over sodium sulfate treated with charcoal filtered evaporated under vacuum

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3 g of D-xylose, 1.9 g of ethylurea, 0.3 g of nitroaniline and 0.2 ml of a concentrated hydrochloric acid is refluxed in 15 ml of ethanol for 10 minutes. The precipitate in the amount of 2.8 g is separated, then added with 15 ml of glacial acetic acid, 2.5 ml of distilled water and 1.74 g of sodium nitrite and stirred for 2 hours at 0° C. The solution is evaporated and recrystallized from an alcohol to give 2.54 g (80% of the theoretical) of the product. M.p. 104° C. (decomposition), [α]D -13.6° (water), Rf =0.76. Found, %: N 16,42. Calculated, %: N 16.86. The precipitate in the amount of 2.8 g is separated added with 15 ml of glacial acetic acid, 2.5 ml of distilled water and 1.74 g of sodium nitrite The solution is evaporated recrystallized from an alcohol to give 2.54 g (80% of the theoretical) of the product

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

Procedure: By the procedures of Example 4, 5.3 g (60 mmol) of ethyl urea was reacted with 10.9 g (50 mmol) of ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 140°-150° C. for 24 hours. The product mixture was treated with methylene chloride, washed with water, dried and concentrated. The residue was recrystallized from methylcyclohexane to yield 8.0 g of crystal product (m.p.=89°-90° C.) identified in Table I. washed with water dried concentrated The residue was recrystallized from methylcyclohexane

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound ii (210 mg, 0.53 mmol) and N-ethylurea (93 mg, 1.1 mmol) were dissolved in degassed dioxane (2 mL) under an atmosphere of nitrogen. Sodium tert-butoxide (102 mg, 1.1 mmol), X-phos (2-(Dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl, 50 mg, 0.1 mmol) and palladium(0)bis(dibenzylideneacetone) (50 mg, 0.05 mmol) were added sequentially. The mixture was heated at 120° C. in a microwave reactor for 60 min. The mixture was cooled to RT, filtered then evaporated to dryness. The residue was purified by flash chromatography (40 g GraceResolv silica cartridge, 0-15% MeOH in DCM) to yield Compound 15 as an off white solid (160 mg, 68%). 1H NMR (400 MHz, DMSO-d6): δ 10.53 (s, 1H), 10.06 (s, 1H), 9.24 (s, 1H), 8.86 (s, 1H), 8.64 (s, 1H), 8.32 (d, J=4.8 Hz, 1H), 8.12 (d, J=7.6 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.80 (m, 1H), 7.55 (s, 1H), 7.40 (d, J=8.8 Hz, 311), 4.32-4.27 (m, 2H), 3.17-3.14 (m, 2H), 1.34 (t, J=7.2 Hz, 3H), 1.12-1.09 (m, 3H). [M+H]+ m/z=449.16. The mixture was cooled to RT filtered then evaporated to dryness The residue was purified by flash chromatography (40 g GraceResolv silica cartridge, 0-15% MeOH in DCM)

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

Procedure: Compound ii (1.0 g, 3.7 mmol) and N-ethylurea (362 mg, 4.1 mmol) were dissolved in degassed dioxane (50 mL) under an atmosphere of argon. Potassium tert-butoxide (628 mg, 5.6 mmol), Xantphos (129 mg, 0.22 mmol) and palladium(0)bis(dibenzylideneacetone) (65 mg, 0.11 mmol) were added sequentially. The mixture was heated at 100° C. with stirring under argon for 16 h. Additional palladium(0)bis(dibenzylideneacetone) (65 mg, 0.11 mmol) and N-ethylurea (560 mg, 6.4 mmol) were added and the mixture heated at reflux for 5 h. The mixture was cooled to RT, diluted with acetonitrile (100 mL) and then adsorbed on to silica by concentration in vacuo. The crude product was purified by flash chromatography (40 g GraceResolv silica cartridge, 0-10% MeOH in EtOAc) to afford iii as a light brown solid (244 mg, 20%). [M+H]+ m/z=320.05. the mixture heated at reflux for 5 h The mixture was cooled to RT adsorbed on to silica by concentration in vacuo The crude product was purified by flash chromatography (40 g GraceResolv silica cartridge, 0-10% MeOH in EtOAc)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ii (6.40 g, 23.18 mmol) in 1,4-dioxane (200 mL) was added N-ethylurea (2.60 g, 29.0 mmol) followed by Cs2CO3 (11.50 g, 34.80 mmol). The resulting solution was purged with nitrogen for 15 min followed by addition of Pd(OAc)2 (0.16 g, 0.70 mmol) and Xantphos (0.81 g, 1.40 mmol). The reaction mixture was again purged with nitrogen for 15 min and then heated at 80° C. for 16 h. The reaction mass was cooled to room temperature and filtered through a celite bed. The celite bed was washed with EtOAc and the combined filtrates concentrated under reduced pressure. Water was added to the residue and extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over silica gel (60-120 M, 50-75% EtOAc-hexane) to obtain a solid residue. This was purified further by trituration with 25% ether-hexane to afford compound iii as an off-white solid (7.0 g, 92%). 1H-NMR (400 MHz, DMSO-d6): δ 9.14 (s, 1H) and 9.64 (s, 1H), 8.61 (s, 1H), 7.70 (br s, 1H), 7.27-7.45 (m, 5H), 7.21 (t, J=7.20 Hz, 1H), 4.32 (q, J=7.20 Hz, 2H), 3.11 (m, 2H), 1.34 (t, J=7.20 Hz, 3H), 1.04 (t, J=7.20 Hz, 3H). [M+H]+ m/z=329.14. The resulting solution was purged with nitrogen for 15 min The reaction mixture was again purged with nitrogen for 15 min The reaction mass was cooled to room temperature filtered through a celite bed The celite bed was washed with EtOAc the combined filtrates concentrated under reduced pressure Water was added to the residue extracted with EtOAc (3×20 mL) The combined organic phase was washed with brine dried (Na2SO4) filtered concentrated under reduced pressure The crude residue was purified over silica gel (60-120 M, 50-75% EtOAc-hexane) to obtain a solid residue This was purified further by trituration with 25% ether-hexane

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

Procedure: Palladium (II) acetate (0.240 g, 1.06 mmol) was added to a solution of Xantphos (0.88 g, 1.52 mmol) in degassed 1,4-dioxane (40 mL) at room temperature. The mixture was stirred under N2(g) for 1 h and treated with iii (0.98 g, 3.54 mmol), N-ethylurea (0.470 g, 5.31 mmol), potassium tert-butoxide (0.600 g, 5.31 mmol) and degassed water (96 μL, 5.31 mmol). The mixture was warmed to 100° C. for 2 h, cooled to room temperature and diluted with EtOAc (50 mL). The mixture was poured onto water (50 mL), and the layers separated. The aqueous phase was further extracted with EtOAc (2×50 mL). The combined organic phase was washed with brine (50 mL), dried (MgSO4) and reduced in vacuo to give the crude product as a brown solid. Column chromatography (SiO2), eluting with 1% MeOH in DCM, afforded compound iv (0.501 g, 1.52 mmol, 43%) as an orange solid. 1H NMR (300 MHz, DMSO-d6): δ 10.14 (1H, br s), 9.94 (1H, br s), 8.77-8.74 (2H, m), 7.64 (2H, d, J 7.7), 7.43 (2H, t, J 8.2), 7.20 (1H, t, J 7.7), 4.35 (2H, q, J 7.2), 3.03 (2H, dq, J 5.6 and 7.2), 1.34 (3H, t, J 7.2), 0.88 (3H, t, J 7.2); [M+H]+ m/z=330.1. cooled to room temperature The mixture was poured onto water (50 mL) the layers separated The aqueous phase was further extracted with EtOAc (2×50 mL) The combined organic phase was washed with brine (50 mL) dried (MgSO4) to give the crude product as a brown solid Column chromatography (SiO2), eluting with 1% MeOH in DCM

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

Procedure: A flask was charged with ethyl 2-cyano-3-methylbutanoate (3b, 20.72 g, 133.5 mmol), ethyl urea (3a, 12.35 g, 140.2 mmol) and MeOH (97.2 mL). To the slurry at room temperature was added sodium methoxide in methanol (25% w/w soln, 36.8 mL), mild exotherm detected. The heterogeneous reaction mixture was then heated to reflux. The reaction was refluxed for 4-12 h. Upon reaction completion, as determined by TLC analysis, the reaction mixture was concentrated and solvent exchanged to acetonitrile (ACN) through 3×50 mL co-evaporations leaving a basic 1-2 vol. solution in ACN. To the reaction mixture was added 1-2 vol. of water followed by a pH adjustment with 2N HCl (aq.). As the pH approached 10, white to off-with solids began forming and, as the pH was further reduced to 3 to 4, (by pH paper) white slurry resulted. This slurry was aged for 0.5 to 24 h and then filtered. The resulting solids were washed with 1 vol. of water and 2×2 vol. MTBE. The white to off-white solids were then dried in a vacuum oven at 40 to 50° C. giving 18.63 g (60%) of 1-ethyl-5-isopropyl-6-amino uracil 2 (HCl salt). The heterogeneous reaction mixture was then heated to reflux The reaction was refluxed for 4-12 h Upon reaction completion the reaction mixture was concentrated leaving a basic 1-2 vol. solution in ACN white to off-with solids began forming and, as the pH resulted filtered The resulting solids were washed with 1 vol. of water and 2×2 vol. MTBE The white to off-white solids were then dried in a vacuum oven at 40 to 50° C.

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

Procedure: A flask was charged with ethyl 2-cyano-3-methylbutanoate (3b, 10.0 g, 64.4 mmol), ethyl urea (3a, 5.96 g, 67.6 mmol) and EtOH (129 mL). To the slurry at room temperature was added sodium ethoxide in ethanol (21% w/w soln, 28.8 mL), mild exotherm detected. The heterogeneous reaction mixture was then heated to reflux. The reaction was refluxed for 4 to 12 h. Upon reaction completion, as determined by TLC analysis, the reaction mixture was concentrated and solvent exchanged to acetonitrile (ACN) through 3×20 mL co-evaporations leaving a basic 1-2 vol. solution in ACN. To the reaction mixture was added 1-2 vol. of water followed by a pH adjustment with 2N HCl (aq.). As the pH approached 10 white to off-with solids began forming and as the pH was further reduced to 9 (by pH paper) white slurry resulted. This slurry was aged for 0.5-24 h and then filtered. The resulting solids were washed with 1 vol. of water and 2×2 vol. MTBE. The white to off-white solids were then dried in a vacuum oven at 40-50° C. giving 4.99 g (39%) of 1-ethyl-5-isopropyl-6-amino uracil 2: The heterogeneous reaction mixture was then heated to reflux The reaction was refluxed for 4 to 12 h Upon reaction completion the reaction mixture was concentrated leaving a basic 1-2 vol. solution in ACN began forming and as the pH resulted filtered The resulting solids were washed with 1 vol. of water and 2×2 vol. MTBE The white to off-white solids were then dried in a vacuum oven at 40-50° C.

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

Procedure: To a solution of 127.5 g (1.5 mol) cyanoacetic acid and 200 ml of acetic anhydride was added 120 g (1.36 mol) of ethylurea. The solution was stirred at 60°-70° C. for 2 hours. After cooling, white crystals were filtered off and washed with ethanol. Yield 153 g (74%) (I). This was stirred in 1 liter of hot water and 160 ml of 2 N NaOH was added in portions so the solution the whole time was basic. The reaction mixture was refluxed for 20 minutes and then neutralized with 5 N HCl. After cooling, white crystals were filtered off. Yield 100 g (65%) (II) NMR. After cooling white crystals were filtered off washed with ethanol This was stirred in 1 liter of hot water 160 ml of 2 N NaOH was added in portions so the solution the whole time The reaction mixture was refluxed for 20 minutes After cooling white crystals were filtered off

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

Procedure: In 50 ml of anhydrous dioxane, 3.5 g (0.04 mol) of ethyl urea was dissolved, and under stirring 4.8 g (0.04 mol) of phenylisocyanate was added thereinto. The reaction was carried out at a room temperature for 15 hours, then the solvent was removed by distillation under a reduced pressure. The residue thus obtained was recrystallized from ethanol-water to obtain 4.6 g (yield 55%) of 1-ethyl-5-phenylbiuret having a melting point of 80°-81.5° C. was added the solvent was removed by distillation under a reduced pressure The residue thus obtained was recrystallized from ethanol-water