ethyl 3-(phenylmethoxycarbonylamino)propanoate

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: To a suspension of sodium hydride (1.92 g, 60% in Oil) in a mixture of tetrahydrofuran (200 ml) and N,N-dimethylformamide (50 ml) was added dropwise ethyl 3-(benzyloxycarbonylamino)propionate (10 g) at 30° C. under nitrogen atmosphere, which was stirred for 30 minutes. To the reaction mixture was added methyl iodide (3 ml) and stirred for additional 6 hours. To the resulting mixture was added carefully water (5 ml), which was poured into a mixture of ethyl acetate (500 ml), n-hexane (150 ml) and water (100 ml). Organic layer was separated, washed n turn with water (100 ml×3), 1N-aqueous hydrochloric acid (100 ml), brine (100 ml), saturated sodium hydrogen carbonate in water (100 ml) and brine (100 ml×2), and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (250 ml) eluting In turn with n-hexane, 10%, 50% ethyl acetate in n-hexane to give ethyl 3-(N-benzyloxycarbonyl-N-methylamino)propionate (8.32 g). stirred for additional 6 hours Organic layer was separated washed n dried over magnesium sulfate Evaporation of the solvent gave a residue, which was chromatographed on silica gel (250 ml) eluting In turn with n-hexane, 10%, 50% ethyl acetate in n-hexane

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

実験手順: To a suspension of sodium hydride (1.92 g, 60% in Oil) in a mixture of tetrahydrofuran (200 ml) and N,N-dimethylformamide (50 ml) was added dropwise ethyl 3-(benzyloxycarbonylamino)propionate (10 g) at 30° C. under nitrogen atmosphere, which was stirred for 30 minutes. To the reaction mixture was added methyl iodide (3 ml) and stirred for additional 6 hours. To the resulting mixture was added carefully water (5 ml), which was poured into a mixture of ethyl acetate (500 ml), n-hexane (150 ml) and water (100 ml). Organic layer was separated, washed n turn with water (100 ml×3), 1N-aqueous hydrochloric acid (100 ml), brine (100 ml), saturated sodium hydrogen carbonate in water (100 ml) and brine (100 ml×2), and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (250 ml) eluting In turn with n-hexane, 10%, 50% ethyl acetate in n-hexane to give ethyl 3-(N-benzyloxycarbonyl-N-methylamino)propionate (8.32 g). stirred for additional 6 hours Organic layer was separated washed n dried over magnesium sulfate Evaporation of the solvent gave a residue, which was chromatographed on silica gel (250 ml) eluting In turn with n-hexane, 10%, 50% ethyl acetate in n-hexane

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

実験手順: Ethyl 3-aminopropionate hydrochloride (10 g) was dissolved in a mixture of tetrahydrofuran (100 ml) and water, which was cooled at 0 to 5° C. in an ice bath and adjusted to pH 8.2 with 30% aqueous sodium hydroxide solution. To a resulting solution was added with care benzyloxycarbonyl chloride (10.3 ml), with maintaining the pH from pH 8.0 to 9.0 with 30% aqueous sodium hydroxide solution at 0 to 5° C. The reaction mixture was extracted with ethyl acetate (300 ml) and organic layer was separated, which was washed two times with saturated sodium chloride in water and dried over magnesium sulfate. Solvent was removed under reduced pressure to give ethyl 3-(benzyloxycarbonylamino)-propionate (15.3 g). The reaction mixture was extracted with ethyl acetate (300 ml) and organic layer was separated which was washed two times with saturated sodium chloride in water dried over magnesium sulfate Solvent was removed under reduced pressure

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

実験手順: Ethyl 3-aminopropionate hydrochloride (10 g) was dissolved in a mixture of tetrahydrofuran (100 ml) and water, which was cooled at 0 to 5° C. in an ice bath and adjusted to pH 8.2 with 30% aqueous sodium hydroxide solution. To a resulting solution was added with care benzyloxycarbonyl chloride (10.3 ml), with maintaining the pH from pH 8.0 to 9.0 with 30% aqueous sodium hydroxide solution at 0 to 5° C. The reaction mixture was extracted with ethyl acetate (300 ml) and organic layer was separated, which was washed two times with saturated sodium chloride in water and dried over magnesium sulfate. Solvent was removed under reduced pressure to give ethyl 3-(benzyloxycarbonylamino)-propionate (15.3 g). The reaction mixture was extracted with ethyl acetate (300 ml) and organic layer was separated which was washed two times with saturated sodium chloride in water dried over magnesium sulfate Solvent was removed under reduced pressure

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

実験手順: 3-Benzyloxycarbonylamino-propionic acid ethyl ester (6.68 g, 26.58 mmol) was dissolved in tetrahydrofuran (40 mL) to which LiHMDS (28 mL, 28 mmol, 1.0 M in THF) was slowly added. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (3.15 g, 13.29 mmol) was then added neat and the reaction mixture was brought to reflux for 7 hours. The reaction mixture was diluted with ethyl acetate and water, the layers separated, the organic layer dried over MgSO4 and the solvent evaporated to give a crude oil. The crude oil was purified by silica gel chromatography to give (8-cyclopentyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-ylmethyl)-carbamic acid benzyl ester as pale yellow waxy solid (1.67 g, 29.6%). 1H NMR δ(400 MHz, CDCl3) 8.57 (s, 1H), 7.56 (s, 1H), 7.26-7.36 (m, 5H), 5.93 (m, 1H), 5.56 (t, J=6.1 Hz, 1H), 5.08 (s, 2H), 4.25 (d, J=6.2 Hz, 2H), 2.60 (s, 3H), 2.30 (m, 2H), 2.05 (m, 2H), 1.86 (m, 2H), 1.69 (m, 2H). was slowly added to reflux for 7 hours the layers separated the organic layer dried over MgSO4 the solvent evaporated to give a crude oil The crude oil was purified by silica gel chromatography

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

実験手順: 3-Benzyloxycarbonylamino-propionic acid ethyl ester (6.68 g, 26.58 mmol) was dissolved in tetrahydrofuran (40 mL) to which LiHMDS (28 mL, 28 mmol, 1.0 M in THF) was slowly added. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (3.15 g, 13.29 mmol) was then added neat and the reaction mixture was brought to reflux for 7 hours. The reaction mixture was diluted with ethyl acetate and water, the layers separated, the organic layer dried over MgSO4 and the solvent evaporated to give a crude oil. The crude oil was purified by silica gel chromatography to give (8-cyclopentyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-ylmethyl)-carbamic acid benzyl ester as pale yellow waxy solid (1.67 g, 29.6%). 1H NMR δ(400 MHz, CDCl3) 8.57 (s, 1H), 7.56 (s, 1H), 7.26-7.36 (m, 5H), 5.93 (m, 1H), 5.56 (t, J=6.1 Hz, 1H), 5.08 (s, 2H), 4.25 (d, J=6.2 Hz, 2H), 2.60 (s, 3H), 2.30 (m, 2H), 2.05 (m, 2H), 1.86 (m, 2H), 1.69 (m, 2H). was slowly added to reflux for 7 hours the layers separated the organic layer dried over MgSO4 the solvent evaporated to give a crude oil The crude oil was purified by silica gel chromatography

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

実験手順: To a suspension of sodium hydride (1.92 g, 60% in Oil) in a mixture of tetrahydrofuran (200 ml) and N,N-dimethylformamide (50 ml) was added dropwise ethyl 3-(benzyloxycarbonylamino)propionate (10 g) at 30° C. under nitrogen atmosphere, which was stirred for 30 minutes. To the reaction mixture was added methyl iodide (3 ml) and stirred for additional 6 hours. To the resulting mixture was added carefully water (5 ml), which was poured into a mixture of ethyl acetate (500 ml), n-hexane (150 ml) and water (100 ml). Organic layer was separated, washed in turn with water (100 ml×3), 1N-aqueous hydrochloric acid (100 ml), brine (100 ml), saturated sodium hydrogen carbonate in water (100 ml) and brine (100 ml×2), and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (250 ml) eluting in turn with n-hexane, 10%, 50% ethyl acetate in n-hexane to give ethyl 3-(N-benzyloxycarbonyl-N-methylamino)propionate (8.32 g). stirred for additional 6 hours Organic layer was separated washed in turn with water (100 ml×3), 1N-aqueous hydrochloric acid (100 ml), brine (100 ml), saturated sodium hydrogen carbonate in water (100 ml) and brine (100 ml×2) dried over magnesium sulfate Evaporation of the solvent gave a residue, which was chromatographed on silica gel (250 ml) eluting in turn with n-hexane, 10%, 50% ethyl acetate in n-hexane

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

実験手順: Ethyl 3-aminopropionate hydrochloride (10 g) was dissolved in a mixture of tetrahydrofuran (100 ml) and water, which was cooled at 0° to 5° C. in an ice bath and adjusted to pH 8.2 with 30% aqueous sodium hydroxide solution. To a resulting solution was added with care benzyloxycarbonyl chloride (10.3 ml), with maintaining the pH from pH 8.0 to 9.0 with 30% aqueous sodium hydroxide solution at 0° to 5° C. The reaction mixture was extracted with ethyl acetate (300 ml) and organic layer was separated, which was washed two times with saturated sodium chloride in water and dried over magnesium sulfate. Solvent was removed under reduced pressure to give ethyl 3-(benzyloxycarbonylamino)-propionate (15.3 g). was cooled at 0° to 5° C. in an ice bath The reaction mixture was extracted with ethyl acetate (300 ml) and organic layer was separated which was washed two times with saturated sodium chloride in water dried over magnesium sulfate Solvent was removed under reduced pressure

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

実験手順: Ethyl 3-aminopropionate hydrochloride (10 g) was dissolved in a mixture of tetrahydrofuran (100 ml) and water, which was cooled at 0° to 5° C. in an ice bath and adjusted to pH 8.2 with 30% aqueous sodium hydroxide solution. To a resulting solution was added with care benzyloxycarbonyl chloride (10.3 ml), with maintaining the pH from pH 8.0 to 9.0 with 30% aqueous sodium hydroxide solution at 0° to 5° C. The reaction mixture was extracted with ethyl acetate (300 ml) and organic layer was separated, which was washed two times with saturated sodium chloride in water and dried over magnesium sulfate. Solvent was removed under reduced pressure to give ethyl 3-(benzyloxycarbonylamino)-propionate (15.3 g). was cooled at 0° to 5° C. in an ice bath The reaction mixture was extracted with ethyl acetate (300 ml) and organic layer was separated which was washed two times with saturated sodium chloride in water dried over magnesium sulfate Solvent was removed under reduced pressure

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

実験手順: 3-Benzyloxycarbonylamino-propionic acid ethyl ester (6.68 g, 26.58 mmol) was dissolved in tetrahydrofuran (40 mL) to which LiHMDS (28 mL, 28 mmol, 1.0 M in THF) was slowly added. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (3.15 g, 13.29 mmol) was then added neat and the reaction mixture was brought to reflux for 7 hours. The reaction mixture was diluted with ethyl acetate and water, the layers separated, the organic layer dried over MgSO4 and the solvent evaporated to give a crude oil. The crude oil was purified by silica gel chromatography to give (8-cyclopentyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-ylmethyl)-carbamic acid benzyl ester as pale yellow waxy solid (1.67 g, 29.6%). 1H NMR δ (400 MHz, CDCl3) 8.57 (s, 1H), 7.56 (s, 1H), 7.26-7.36 (m, 5H), 5.93 (m, 1H), 5.56 (t, J=6.1 Hz, 1H), 5.08 (s, 2H), 4.25 (d, J=6.2 Hz, 2H), 2.60 (s, 3H), 2.30 (m, 2H), 2.05 (m, 2H), 1.86 (m, 2H), 1.69 (m, 2H). was slowly added to reflux for 7 hours the layers separated the organic layer dried over MgSO4 the solvent evaporated to give a crude oil The crude oil was purified by silica gel chromatography

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

実験手順: To a suspension of sodium hydride (1.92 g, 60% in Oil) in a mixture of tetrahydrofuran (200 ml) and N,N-dimethylformamide (50 ml) was added dropwise ethyl 3-(benzyloxycarbonylamino)propionate (10 g) at 30° C. under nitrogen atmosphere, which was stirred for 30 minutes. To the reaction mixture was added methyl iodide (3 ml) and stirred for additional 6 hours. To the resulting mixture was added carefully water (5 ml), which was poured into a mixture of ethyl acetate (500 ml), n-hexane (150 ml) and water (100 ml). Organic layer was separated, washed n turn with water (100 ml×3), 1N-aqueous hydrochloric acid (100 ml), brine (100 ml), saturated sodium hydrogen carbonate in water (100 ml) and brine (100 ml×2), and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (250 ml) eluting In turn with n-hexane, 10%, 50% ethyl acetate in n-hexane to give ethyl 3-(N-benzyloxycarbonyl-N-methylamino)propionate (8.32 g). stirred for additional 6 hours Organic layer was separated washed n dried over magnesium sulfate Evaporation of the solvent gave a residue, which was chromatographed on silica gel (250 ml) eluting In turn with n-hexane, 10%, 50% ethyl acetate in n-hexane