tert-butyl N-[(2S)-1-oxopropan-2-yl]carbamate

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

実験手順: Boc-L-alanine methyl ester (5.0 g, 24.6 mmol) was dissolved in dry toluene (150 ml) under an argon atmosphere and cooled in a dry ice-acetone bath. To this vigorously stirred solution was added a solution of diisobutylaluminumhydride (1.0 M in hexanes, 61.5 ml, 61.5 mmol), pre-cooled in a dry ice-acetone bath, via a transfer needle. After 6 minutes, the reaction was carefully quenched with methanol (4 ml) and the mixture allowed to warm to room temperature. The reaction mixture was poured into a separatory funnel containing 250 ml ether and 200 ml of ice cold 0.25 N hydrochloric acid. The layers were separated and the organic layer was washed with 0.25 N hydrochloric acid (3×80 ml) and brine (50 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated using a rotary evaporator at ambient temperature. The residue was chromatographed using hexanes--30% ethyl-acetate to give Boc-L-alaninal. The compound may also be prepared by the technique described in Synthesis, 1983, pg. 676. cooled in a dry ice-acetone bath pre-cooled in a dry ice-acetone bath, via a transfer needle the reaction was carefully quenched with methanol (4 ml) The reaction mixture was poured into a separatory funnel containing 250 ml ether and 200 ml of ice cold 0.25 N hydrochloric acid The layers were separated the organic layer was washed with 0.25 N hydrochloric acid (3×80 ml) and brine (50 ml) The organic layer was dried over magnesium sulfate filtered concentrated a rotary evaporator at ambient temperature The residue was chromatographed

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

実験手順: (S)-(−)-2-(tert-Butoxycarbonylamino)-1-propanol (523 mg, 2.98 mmol, 1.0 equiv.) was dissolved in 45 mL methylene chloride in a 100 mL r.b. flask with a magnetic stir bar. To this clear homogeneous solution, Dess-Martin periodinane (1.523 g, 3.591 mmol, 1.2 equiv.) was added in one part and the cloudy white reaction mixture was allowed to stir at room temperature for 2 h. Thin-layer chromotography monitored the reaction to completion. The reaction mixture was diluted with 100 mL ethyl acetate. Sodium bisulfite solution (2 M, 20 mL) was added to the reaction mixture and the organic layer was separated. The aqueous layer was washed with 3×30 mL EtOAc. The combined organic layers were washed with 50 mL 1 M NaOH, followed by saturated NaCl (30 mL) and dried over MgSO4. Filtration and rotary evaporation produced the desired product as a yellow oil (475 mg, 92% yield, Rf=0.63, 1:1 hexanes/ethyl acetate). Step B: Preparation of [2-(4-methoxy-phenylamino)-(1S)-methyl-ethyl]-carbamic acid tert-butyl ester. (S)-2-(tert-Butoxycarbonylamino)-propionaldehyde (473 mg, 2.74 mmol) and p-anisidine (1.031 g, 8.371 mmol, 3.0 equiv.) was dissolved in 45 mL of MeOH at 0° C. in a 100 mL r.b. flask with a magnetic stir bar. Optionally, acetic acid (469 μL, 8.21 mmol, 3.0 equiv.) can be added via syringe to assist in the reaction. To the stirring dark colored solution was added sodium cyanoborohydride (326 mg, 5.82 mmol, 1.89 equiv.). Gas evolution and disappearance of color were observed. The reaction was allowed to slowly warm to room temperature with stirring over 30 minutes and the reaction was monitored by LC/MS. At the completion of the reaction, the mixture was quenched with 1 M NaOH, and extracted 3×50 mL ethyl acetate. The resulting organics were washed with 50 mL saturated NaHCO3, 40 mL saturated NaCl, and dried over MgSO4. Evaporation of ethyl acetate provided 728 mg of a brown oil. Purification by automated ISCO chromatography provided a clear oil of [2-(4-methoxy-phenylamino)-(1S)-methyl-ethyl]-carbamic acid tert-butyl ester (583 mg, 2.079 mmol, 76% yield). HPLC-MS calcd. for C15H24N2O3 (M+H+) 281.2. found 281.5. 1H NMR (CDCl3, 400 MHz) δ 1.21 (d, 6H, J=6.6 Hz), 1.47 (s, 9H), 3.05 (dd, 1H, J=12.2, 7.3 Hz), 3.13 (dd, 1H, J=12.2, 4.6 Hz), 3.76 (s, 3H), 3.93 (broad s, 1H), 4.62 (broad s, 1H), 6.60 (d, 2H, J=6.8 Hz), 6.80 (2H, d, J=6.8 Hz). Step C: [2-(4-Methoxy-phenylamino)-(1S)-methyl-ethyl]-carbamic acid tert-butyl ester (383 mg, 1.37 mmol) was added to 10 mL of a trifluroacetic acid solution (10 v/v % in methylene chloride) at room temperature in a 25 mL r.b. flask with a magnetic stirbar. The reaction turns dark purple/black in color after 5 minutes. The reaction is allowed to stir at room temperature until the reaction is judged complete by HPLC/MS. The solvent is removed by evaporation and to provide 2-(4-Methoxy-phenylamino)-(1S)-methyl-ethyl-ammonium trifluoroacetate salt as a brown oil (394 mg, 1.34 mmol, 98% yield) and used directly in the next reaction. HPLC-MS calcd. for C10H16N2O (M+H+) 181.1. found 181.5. the reaction to completion the organic layer was separated The aqueous layer was washed with 3×30 mL EtOAc The combined organic layers were washed with 50 mL 1 M NaOH dried over MgSO4 Filtration and rotary evaporation

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

実験手順: (S)-(−)-2-(tert-Butoxycarbonylamino)-1-propanol (523 mg, 2.98 mmol, 1.0 equiv.) was dissolved in 45 mL methylene chloride in a 100 mL r.b. flask with a magnetic stir bar. To this clear homogeneous solution, Dess-Martin periodinane (1.523 g, 3.591 mmol, 1.2 equiv.) was added in one part and the cloudy white reaction mixture was allowed to stir at room temperature for 2 h. Thin-layer chromotography monitored the reaction to completion. The reaction mixture was diluted with 100 mL ethyl acetate. Sodium bisulfite solution (2 M, 20 mL) was added to the reaction mixture and the organic layer was separated. The aqueous layer was washed with 3×30 mL EtOAc. The combined organic layers were washed with 50 mL 1 M NaOH, followed by saturated NaCl (30 mL) and dried over MgSO4. Filtration and rotary evaporation produced the desired product as a yellow oil (475 mg, 92% yield, Rf=0.63, 1:1 hexanes/ethyl acetate). the reaction to completion the organic layer was separated The aqueous layer was washed with 3×30 mL EtOAc The combined organic layers were washed with 50 mL 1 M NaOH dried over MgSO4 Filtration and rotary evaporation

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

実験手順: To a stirred solution of (S)-tert-butyl (1-oxopropan-2-yl)carbamate (3.15 g, 18.18 mmol), and DCM (91 ml) was added 2-amino-3,3,3-trifluoropropan-1-ol (2.230 g, 17.28 mmol). Stirred at ambient temperature for 10 minutes and then added sodium triacetoxyborohydride (5.78 g, 27.3 mmol). The mixture was stirred overnight. The reaction was diluted with DCM and then washed with 1 N NaOH, brine dried over MgSO4, filtered and the solvent removed to provide 4.0 grams of tert-butyl ((2S)-1-((1,1,1-trifluoro-3-hydroxypropan-2-yl)amino)propan-2-yl)carbamate as a colorless oil that was used without further purification. LRMS m/z (M+H)+ 287.3 found, 287.3 required. The mixture was stirred overnight washed with 1 N NaOH, brine dried over MgSO4 filtered the solvent removed

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

実験手順: (S)-(−)-2-(tert-Butoxycarbonylamino)-1-propanol (523 mg, 2.98 mmol, 1.0 equiv.) was dissolved in 45 mL methylene chloride in a 100 mL r.b. flask with a magnetic stir bar. To this clear homogeneous solution, Dess-Martin periodinane (1.523 g, 3.591 mmol, 1.2 equiv.) was added in one part and the cloudy white reaction mixture was allowed to stir at room temperature for 2 h. Thin-layer chromotography monitored the reaction to completion. The reaction mixture was diluted with 100 mL ethyl acetate. Sodium bisulfite solution (2 M, 20 mL) was added to the reaction mixture and the organic layer was separated. The aqueous layer was washed with 3×30 mL EtOAc. The combined organic layers were washed with 50 mL 1 M NaOH, followed by saturated NaCl (30 mL) and dried over MgSO4. Filtration and rotary evaporation produced the desired product as a yellow oil (475 mg, 92% yield, Rf=0.63, 1:1 hexanes/ethyl acetate). the reaction to completion the organic layer was separated The aqueous layer was washed with 3×30 mL EtOAc The combined organic layers were washed with 50 mL 1 M NaOH dried over MgSO4 Filtration and rotary evaporation

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

実験手順: 2-(S)-[N-(tert-Butoxycarbonyl)amino]propanal was prepared from L-alanine according to the procedure described in the literature (Chakravarty et al, J. Med. Chem 1989, p1886). A mixture of the aldehyde (2.62 g), dimethylamine hydrochloride (2.47 g), sodium acetate (1.99 g) and sodium cyanoborohydride (1.43 g) in methanol (45 mL) was stirred at room temperature for 8 hours. The reaction mixture was dissolved in ethyl acetate, washed with water, dried (MgSO4), and the solvent removed in vacuo to yield a viscous oil. This was dissolved in dichloromethane, extracted with citric acid, basified with sodium hydroxide, and re-extracted with ethyl acetate. The organic layer was reduced in vacuo to yield the dimethylamino derivative as a white solid (586 mg). washed with water dried (MgSO4) the solvent removed in vacuo to yield a viscous oil extracted with citric acid re-extracted with ethyl acetate

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

実験手順: 6.82 g (60 mmoles) of cysteamine hydrochloride is dissolved in 50 ml of dimethylformamide, and the solution is neutralized with 8.4 ml of triethylamine. The solution is mixed with a solution of crude Boc-L-alaninal obtained by oxidizing 8.75 g (50 mmoles) of Boc-alaninol in 50 ml of dimethylformamide, and mixture is stirred overnight at room temperature. The solvent is distilled off under reduced pressure, the formed crystals are dissolved in ethyl acetate, the solution is washed with 10% citric acid and saturated aqueous sodium bicarbonate, and the ethyl acetate layer is dried. The solvent is distilled off under reduced pressure to obtain 4.93 g (42.6%) of the desired compound 9-A as white crystals.

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

実験手順: (S)-1-Methyl-3-phenylpropanamine hydrochloride was prepared by first esterifying N-(tert-butyloxycarbonyl)-L-alanine with diazomethane, then reducing the resulting N-(tert-butyloxycarbonyl)-L-alanine methyl ester with diisobutylaluminum hydride, then condensing the resulting N-(tert -butyloxycarbonyl)-L-alaninal with benzylidenetriphenylphosphonium ylide, then hydrogenating over palladium catalyst the resulting [S-(E)]-N-(tert-butyloxycarbonyl)-1-methyl-3-phenyl-2-propenamine having m.r. 86°-88° C. and [α]D25 (c=1, methanol) -50.9°, and finally deprotecting with hydrogen chloride in dioxane the resulting (S)-N-(tert-butyloxycarbonyl)-1-methyl-3-phenylpropanamine having m.r. 78°-80° C. and [α]D25 -7.1° (c=1, methanol). ##STR13##

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

実験手順: (S)-1-Methyl-3-phenylpropanamine hydrochloride was prepared by first esterifying N-(tert-butyloxycarbonyl)-L-alanine with diazomethane, then reducing the resulting N-(tert-butyloxycarbonyl)-L-alanine methyl ester with diisobutylaluminum hydride, then condensing the resulting N-(tert -butyloxycarbonyl)-L-alaninal with benzylidenetriphenylphosphonium ylide, then hydrogenating over palladium catalyst the resulting [S-(E)]-N-(tert-butyloxycarbonyl)-1-methyl-3-phenyl-2-propenamine having m.r. 86°-88° C. and [α]D25 (c=1, methanol) -50.9°, and finally deprotecting with hydrogen chloride in dioxane the resulting (S)-N-(tert-butyloxycarbonyl)-1-methyl-3-phenylpropanamine having m.r. 78°-80° C. and [α]D25 -7.1° (c=1, methanol). ##STR13##

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

実験手順: Boc-L-alanine methyl ester (5.0 g, 24.6 mmol) was dissolved in dry toluene (150 ml) under an argon atmosphere and cooled in a dry ice-acetone bath. To this vigorously stirred solution was added a solution of diisobutylaluminumhydride (1.0 M in hexanes, 61.5 ml, 61.5 mmol), pre-cooled in a dry ice-acetone bath, via a transfer needle. After 6 minutes, the reaction was carefully quenched with methanol (4 ml) and the mixture allowed to warm to room temperature. The reaction mixture was poured into a separatory funnel containing 250 ml ether and 200 ml of ice cold 0.25 N hydrochloric acid. The layers were separated and the organic layer was washed with 0.25 N hydrochloric acid (3×80 ml) and brine (50 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated using a rotary evaporator at ambient temperature. The residue was chromatographed using hexanes--30% ethyl-acetate to give Boc-L-alaninal. The compound may also be prepared by the technique described in Synthesis, 1983, pg. 676. cooled in a dry ice-acetone bath pre-cooled in a dry ice-acetone bath, via a transfer needle the reaction was carefully quenched with methanol (4 ml) The reaction mixture was poured into a separatory funnel containing 250 ml ether and 200 ml of ice cold 0.25 N hydrochloric acid The layers were separated the organic layer was washed with 0.25 N hydrochloric acid (3×80 ml) and brine (50 ml) The organic layer was dried over magnesium sulfate filtered concentrated a rotary evaporator at ambient temperature The residue was chromatographed

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

実験手順: (S)-(−)-2-(tert-Butoxycarbonylamino)-1-propanol (523 mg, 2.98 mmol, 1.0 equiv.) was dissolved in 45 mL methylene chloride in a 100 mL r.b. flask with a magnetic stir bar. To this clear homogeneous solution, Dess-Martin periodinane (1.523 g, 3.591 mmol, 1.2 equiv.) was added in one part and the cloudy white reaction mixture was allowed to stir at room temperature for 2 h. Thin-layer chromotography monitored the reaction to completion. The reaction mixture was diluted with 100 mL ethyl acetate. Sodium bisulfite solution (2 M, 20 mL) was added to the reaction mixture and the organic layer was separated. The aqueous layer was washed with 3×30 mL EtOAc. The combined organic layers were washed with 50 mL 1 M NaOH, followed by saturated NaCl (30 mL) and dried over MgSO4. Filtration and rotary evaporation produced the desired product as a yellow oil (475 mg, 92% yield, Rf=0.63, 1:1 hexanes/ethyl acetate). Step B: Preparation of [2-(4-methoxy-phenylamino)-(1S)-methyl-ethyl]-carbamic acid tert-butyl ester. (S)-2-(tert-Butoxycarbonylamino)-propionaldehyde (473 mg, 2.74 mmol) and p-anisidine (1.031 g, 8.371 mmol, 3.0 equiv.) was dissolved in 45 mL of MeOH at 0° C. in a 100 mL r.b. flask with a magnetic stir bar. Optionally, acetic acid (469 μL, 8.21 mmol, 3.0 equiv.) can be added via syringe to assist in the reaction. To the stirring dark colored solution was added sodium cyanoborohydride (326 mg, 5.82 mmol, 1.89 equiv.). Gas evolution and disappearance of color were observed. The reaction was allowed to slowly warm to room temperature with stirring over 30 minutes and the reaction was monitored by LC/MS. At the completion of the reaction, the mixture was quenched with 1 M NaOH, and extracted 3×50 mL ethyl acetate. The resulting organics were washed with 50 mL saturated NaHCO3, 40 mL saturated NaCl, and dried over MgSO4. Evaporation of ethyl acetate provided 728 mg of a brown oil. Purification by automated ISCO chromatography provided a clear oil of [2-(4-methoxy-phenylamino)-(1S)-methyl-ethyl]-carbamic acid tert-butyl ester (583 mg, 2.079 mmol, 76% yield). HPLC-MS calcd. for C15H24N2O3 (M+H+) 281.2. found 281.5. 1H NMR (CDCl3, 400 MHz) δ 1.21 (d, 6H, J=6.6 Hz), 1.47 (s, 9H), 3.05 (dd, 1H, J=12.2, 7.3 Hz), 3.13 (dd, 1H, J=12.2, 4.6 Hz), 3.76 (s, 3H), 3.93 (broad s, 1H), 4.62 (broad s, 1H), 6.60 (d, 2H, J=6.8 Hz), 6.80 (2H, d, J=6.8 Hz). Step C: [2-(4-Methoxy-phenylamino)-(1S)-methyl-ethyl]-carbamic acid tert-butyl ester (383 mg, 1.37 mmol) was added to 10 mL of a trifluroacetic acid solution (10 v/v % in methylene chloride) at room temperature in a 25 mL r.b. flask with a magnetic stirbar. The reaction turns dark purple/black in color after 5 minutes. The reaction is allowed to stir at room temperature until the reaction is judged complete by HPLC/MS. The solvent is removed by evaporation and to provide 2-(4-Methoxy-phenylamino)-(1S)-methyl-ethyl-ammonium trifluoroacetate salt as a brown oil (394 mg, 1.34 mmol, 98% yield) and used directly in the next reaction. HPLC-MS calcd. for C10H16N2O (M+H+) 181.1. found 181.5. the reaction to completion the organic layer was separated The aqueous layer was washed with 3×30 mL EtOAc The combined organic layers were washed with 50 mL 1 M NaOH dried over MgSO4 Filtration and rotary evaporation

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

実験手順: (S)-(−)-2-(tert-Butoxycarbonylamino)-1-propanol (523 mg, 2.98 mmol, 1.0 equiv.) was dissolved in 45 mL methylene chloride in a 100 mL r.b. flask with a magnetic stir bar. To this clear homogeneous solution, Dess-Martin periodinane (1.523 g, 3.591 mmol, 1.2 equiv.) was added in one part and the cloudy white reaction mixture was allowed to stir at room temperature for 2 h. Thin-layer chromotography monitored the reaction to completion. The reaction mixture was diluted with 100 mL ethyl acetate. Sodium bisulfite solution (2 M, 20 mL) was added to the reaction mixture and the organic layer was separated. The aqueous layer was washed with 3×30 mL EtOAc. The combined organic layers were washed with 50 mL 1 M NaOH, followed by saturated NaCl (30 mL) and dried over MgSO4. Filtration and rotary evaporation produced the desired product as a yellow oil (475 mg, 92% yield, Rf=0.63, 1:1 hexanes/ethyl acetate). the reaction to completion the organic layer was separated The aqueous layer was washed with 3×30 mL EtOAc The combined organic layers were washed with 50 mL 1 M NaOH dried over MgSO4 Filtration and rotary evaporation