methyl (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate

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

Procedure: 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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2,6-dimethyl-N-phenylbenzamide (compound 4403), which may be synthesized as described in Example 9) (30 g, 0.13 mol, 1 eq) and HMPA (26 g, 0.16 mol, 1.2 eq) in anhydrous THF (300 mL) at −78° C. under an argon atmosphere, n-butyllithium (100 mL, 2.5 M, 0.25 mol, 2.5 eq) was added carefully over 1 h and the reaction temperature was kept below −60° C. during addition. The resulting mixture was stirred at −78° C. for 1 h, and then (S)-methyl 2-(tert-butoxycarbonylamino)-propanoate (compound 4803) (35 g, 0.173 mol, 1.3 eq) was quickly added (the reaction temperature rose to −50° C. during addition). The mixture was stirred at −50° C. for 10 min, quenched with water (300 mL) and extracted with ethyl acetate (2×100 mL). The organic layer was washed with water (500 mL×2), dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo to afford the crude product as a semi-solid oil. The crude product was slurried in ethyl acetate (500 mL) and stirred for 10 min. The solid was removed by filtration, and the filtrate was concentrated in vacuo. The oil residue was stirred in a mixture of ethyl acetate (30 mL) and isopropyl alcohol (200 mL) at room temperature for 10 min. The solid was collected by filtration and further dried in vacuo to afford the desired product, tert-butyl4-(3-methyl-2-(phenylcarbamoyl)phenyl)-3-oxobutan-2-ylcarbamate (compound 4703) (4.61 g, 9% yield) as a white solid. at −78° C. the reaction temperature was kept below −60° C. during addition rose to −50° C. during addition) The mixture was stirred at −50° C. for 10 min quenched with water (300 mL) extracted with ethyl acetate (2×100 mL) The organic layer was washed with water (500 mL×2) dried over anhydrous MgSO4 filtered The filtrate was concentrated in vacuo to afford the crude product as a semi-solid oil stirred for 10 min The solid was removed by filtration the filtrate was concentrated in vacuo The oil residue was stirred in a mixture of ethyl acetate (30 mL) and isopropyl alcohol (200 mL) at room temperature for 10 min The solid was collected by filtration further dried in vacuo

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

Procedure: A solution of chloroacetic acid (23.2 g, 246 mmol) in tetrahydrofuran (100 mL) was added over 35 minutes to a −78° C. solution of lithium diisopropylamide in tetrahydrofuran (2.05 M, 240 mL, 492 mmol), at a rate that kept the internal temperature below −65° C. After 30 minutes, the reaction mixture was quickly transferred into a (dry ice)-jacketed addition funnel and added over 5 minutes to a solution of methyl N-(tert-butoxycarbonyl)-L-alaninate (10.0 g, 49.2 mmol) in tetrahydrofuran (120 mL). Mechanical stirring was used for this reaction. The mixture was stirred for 30 minutes, during which time the reaction mixture warmed to 0° C. It was cooled to −78° C. and treated over 10 minutes with a solution of acetic acid (41 mL, 720 mmol) in tetrahydrofuran (41 mL). At this point, the flask was immersed in an ice bath, and stirring was continued for 1.5 hours, while the reaction warmed to 5° C. Water (250 mL) was added, followed by diethyl ether (400 mL); the organic layer was washed with saturated aqueous sodium bicarbonate solution (150 mL) and with saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the product as a waxy, light yellow solid. Yield: 9.47 g, 42.7 mmol, 87%. 1H NMR (400 MHz, CDCl3) δ 5.11 (br d, J=6 Hz, 1H), 4.48-4.58 (m, 1H), 4.28 (AB quartet, JAB=15.9 Hz, ΔνAB=8.3 Hz, 2H), 1.44 (s, 9H), 1.38 (d, J=7.1 Hz, 3H). the internal temperature below −65° C addition funnel was used for this reaction The mixture was stirred for 30 minutes, during which time the reaction mixture It was cooled to −78° C. At this point, the flask was immersed in an ice bath stirring was continued for 1.5 hours, while the reaction warmed to 5° C the organic layer was washed with saturated aqueous sodium bicarbonate solution (150 mL) and with saturated aqueous sodium chloride solution (50 mL) dried over magnesium sulfate filtered concentrated in vacuo to afford the product as a waxy, light yellow solid

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

Procedure: (S)-methyl 2-(tert-butoxycarbonylamino)propanoate (10.0 g, 49.2 mmol) was dissolved in THF (100 mL) and cooled to 0° C. under nitrogen. Sodium hydride (60% susp. in mineral oil, 3.00 g, 75.1 mmol) was added in portions over 2 min. The reaction mixture was stirred for 5 min at 0° C. and EtI (4.80 mL, 59.5 mmol) was added. It was allowed to warm to room temperature over the period of 1 h, stirred at room temperature overnight and at 70° C. for 7 d. The reaction mixture was cooled, filtered and concentrated in vacuo. The solid was triturated with hexanes (2×70 mL), the triturates were concentrated in vacuo and the residue was purified using flash column chromatography on silica gel (330 g SiO2, hexanes:ethyl acetate 19:1-9:1) to afford the title compounds as an oil (4.40 g, 39%). [M+H] calc'd for C11H21NO4, 232. found, 232. to warm to room temperature over the period of 1 h stirred at room temperature overnight and at 70° C. for 7 d The reaction mixture was cooled filtered concentrated in vacuo The solid was triturated with hexanes (2×70 mL) the triturates were concentrated in vacuo the residue was purified

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

Procedure: This compound was prepared in 90% yield from the ester 4a (2.44 g, 12 mmol) by reduction with lithium borohydride in dry DME analogous to the method described earlier1,2. The product was used for the next reaction without further purification. 1H NMR (CDCl3) δ 1.14 (d, J=6.6 Hz, 3H, CHCH3), 1.44 (s, 9H, t-Bu), 2.71 (br s, 1H, CH2OH), 3.45 and 3.55 (AB part of ABX spectrum, 7 lines, JAX =4.7 Hz, JBX =7.4 Hz, JAB =10.1 Hz, 2H, 2H, CH2OH), 3.47-3.95 (m, 1H, CHCH3), 4.68 (br d, 1H, NH). Anal. Calcd. for C8H17NO3 : C, 54.84; H, 9,78; N, 7.99. Found: C, 54.84; H, 9.96; N, 7.96. The product was used for the next reaction without further purification

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

Procedure: (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##

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

Procedure: (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##

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

Procedure: 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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2,6-dimethyl-N-phenylbenzamide (compound 4403), which may be synthesized as described in Example 9) (30 g, 0.13 mol, 1 eq) and HMPA (26 g, 0.16 mol, 1.2 eq) in anhydrous THF (300 mL) at −78° C. under an argon atmosphere, n-butyllithium (100 mL, 2.5 M, 0.25 mol, 2.5 eq) was added carefully over 1 h and the reaction temperature was kept below −60° C. during addition. The resulting mixture was stirred at −78° C. for 1 h, and then (S)-methyl 2-(tert-butoxycarbonylamino)-propanoate (compound 4803) (35 g, 0.173 mol, 1.3 eq) was quickly added (the reaction temperature rose to −50° C. during addition). The mixture was stirred at −50° C. for 10 min, quenched with water (300 mL) and extracted with ethyl acetate (2×100 mL). The organic layer was washed with water (500 mL×2), dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo to afford the crude product as a semi-solid oil. The crude product was slurried in ethyl acetate (500 mL) and stirred for 10 min. The solid was removed by filtration, and the filtrate was concentrated in vacuo. The oil residue was stirred in a mixture of ethyl acetate (30 mL) and isopropyl alcohol (200 mL) at room temperature for 10 min. The solid was collected by filtration and further dried in vacuo to afford the desired product, tert-butyl4-(3-methyl-2-(phenylcarbamoyl)pheny)-3-oxobutan-2-ylcarbamate (compound 4703) (4.61 g, 9% yield) as a white solid. at −78° C. the reaction temperature was kept below −60° C. during addition rose to −50° C. during addition) The mixture was stirred at −50° C. for 10 min quenched with water (300 mL) extracted with ethyl acetate (2×100 mL) The organic layer was washed with water (500 mL×2) dried over anhydrous MgSO4 filtered The filtrate was concentrated in vacuo to afford the crude product as a semi-solid oil stirred for 10 min The solid was removed by filtration the filtrate was concentrated in vacuo The oil residue was stirred in a mixture of ethyl acetate (30 mL) and isopropyl alcohol (200 mL) at room temperature for 10 min The solid was collected by filtration further dried in vacuo

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

Procedure: A solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)propanoate (1.00 g, 4.92 mmol) and hydrazine (0.23 mL, 1.5 equiv) in THF (8 mL) was heated in a sealed tube at 72° C. for 15 hours. Additional hydrazine (0.23 mL, 1.5 equiv) was added and heating was continued for another 21 hours. The reaction was then cooled to room temperature and concentrated in vacuo to give crude (S)-tert-butyl(1-hydrazinyl-1-oxopropan-2-yl)carbamate (1 g, white solid), which was used without purification. 1H NMR (400 MHz, CDCl3) δ 4.20 (m, 1H), 1.44 (s, 9H), 1.36 (d, J=7.1 Hz, 3H). heating concentrated in vacuo

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2,6-dimethyl-N-phenylbenzamide (compound 4403), which may be synthesized as described in Example 9) (30 g, 0.13 mol, 1 eq) and HMPA (26 g, 0.16 mol, 1.2 eq) in anhydrous THF (300 mL) at −78° C. under an argon atmosphere, n-butyllithium (100 mL, 2.5 M, 0.25 mol, 2.5 eq) was added carefully over 1 h and the reaction temperature was kept below −60° C. during addition. The resulting mixture was stirred at −78° C. for 1 h, and then (S)-methyl 2-(tert-butoxycarbonylamino)-propanoate (compound 4803) (35 g, 0.173 mol, 1.3 eq) was quickly added (the reaction temperature rose to −50° C. during addition). The mixture was stirred at −50° C. for 10 min, quenched with water (300 mL) and extracted with ethyl acetate (2×100 mL). The organic layer was washed with water (500 mL×2), dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo to afford the crude product as a semi-solid oil. The crude product was slurried in ethyl acetate (500 mL) and stirred for 10 min. The solid was removed by filtration, and the filtrate was concentrated in vacuo. The oil residue was stirred in a mixture of ethyl acetate (30 mL) and isopropyl alcohol (200 mL) at room temperature for 10 min. The solid was collected by filtration and further dried in vacuo to afford the desired product, tert-butyl4-(3-methyl-2-(phenylcarbamoyl)pheny)-3-oxobutan-2-ylcarbamate (compound 4703) (4.61 g, 9% yield) as a white solid. at −78° C. the reaction temperature was kept below −60° C. during addition rose to −50° C. during addition) The mixture was stirred at −50° C. for 10 min quenched with water (300 mL) extracted with ethyl acetate (2×100 mL) The organic layer was washed with water (500 mL×2) dried over anhydrous MgSO4 filtered The filtrate was concentrated in vacuo to afford the crude product as a semi-solid oil stirred for 10 min The solid was removed by filtration the filtrate was concentrated in vacuo The oil residue was stirred in a mixture of ethyl acetate (30 mL) and isopropyl alcohol (200 mL) at room temperature for 10 min The solid was collected by filtration further dried in vacuo

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

Procedure: A solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)propanoate (1.00 g, 4.92 mmol) and hydrazine (0.23 mL, 1.5 equiv) in THF (8 mL) was heated in a sealed tube at 72° C. for 15 hours. Additional hydrazine (0.23 mL, 1.5 equiv) was added and heating was continued for another 21 hours. The reaction was then cooled to room temperature and concentrated in vacuo to give crude (S)-tert-butyl(1-hydrazinyl-1-oxopropan-2-yl)carbamate (1 g, white solid), which was used without purification. 1H NMR (400 MHz, CDCl3) δ 4.20 (m, 1H), 1.44 (s, 9H), 1.36 (d, J=7.1 Hz, 3H). heating concentrated in vacuo