benzyl (2S)-2-amino-3-methylbutanoate

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

Procedure: To a solution of L-valine benzylester in MeOH (12 mL) was slowly added 1,3-propanesultone (604 mg, 5.0 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with cold MeOH and acetone (2×25 mL). It was dried in the vacuum oven (50° C.), affording the title compound (649 mg, 39%). 1H NMR (D2O, 500 MHz) δ ppm 7.47 (m, 5H), 5.41 (d, 1H, J=11.7 Hz), 5.31 (d, 3H, J=11.7 Hz), 4.04 (m, 1H), 3.19 (m, 2H), 2.95 (t, 2H, J=6.8 Hz), 2.35 (m, 1H), 2.14 (m, 2H), 1.04 (d, 3H, J=6.3 Hz), 0.95 (d, 3H, J=6.3 Hz). 13C (D2O, 125 MHz) δ ppm 168.75, 134.81, 129.38, 129.31, 129.17, 69.00, 65.96, 48.24, 46.71, 29.67, 21.40, 18.39, 16.65. [α]D=−7.2° (c=0.0015 in water), ES-MS 330 (M+1). at reflux for 2 hours The solid was collected by filtration washed with cold MeOH and acetone (2×25 mL) It was dried in the vacuum oven (50° C.)

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

Procedure: N-(4-pentenoyl)valyl-pdCpA was prepared. Treatment of S-valine methyl ester with 4-pentenoic anhydride afforded the respective amide as a colorless oil in 73% yield. Following hydrolysis of the ester moiety (LiOH, aq THF), the derived intermediate was converted to the respective cyanomethyl ester (4). Admixture of 4 and pdCpA Robertson, et al., Nucleic Acids Res. 17:9649 (1989), in freshly distilled DMF afforded N-(4-pentenoyl)valyl-pdCpA (5) as a colorless solid in 94% yield. A sample of N-(2-nitroveratryloxycarbonyl)valyl-pdCpA was prepared as described, Robertson, et al., J. Am. Chem. Soc. 113:2722 (1991) for comparative purposes.

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

Procedure: N-(4-pentenoyl)valyl-pdCpA was prepared. Treatment of S-valine methyl ester with 4-pentenoic anhydride afforded the respective amide as a colorless oil in 73% yield. Following hydrolysis of the ester moiety (LiOH, aq THF), the derived intermediate was converted to the respective cyanomethyl ester (4). Admixture of 4 and pdCpA Robertson, et al., Nucleic Acids Res. 17:9649 (1989), in freshly distilled DMF afforded N-(4-pentenoyl)valyl-pdCpA (5) as a colorless solid in 94% yield. A sample of N-(2-nitroveratryloxycarbonyl)valyl-pdCpA was prepared as described, Robertson, et al., J. Am. Chem. Soc. 113:2722 (1991) for comparative purposes.

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

Procedure: To a solution of methyl p-aminobenzoate (0.4 g) in tetrahydrofuran (10 ml) was added trichloromethylchloroformate (0.31 g) and the mixture was allowed to stand overnight at room temperature. L-Valine benzyl ester (0.54 g) was added to the solution and the pH of the mixture was neutralized with triethylamine. After being stirred for 30 minutes at room temperature, the mixture was concentrated under reduced pressure and the residue was extracted with ethyl acetate (10 ml). The extract was washed with 1N-hydrochloric acid (10 ml) and aqueous sodium bicarbonate (10 ml) and concentrated to dryness to give 4-(methoxycarbonyl)phenylaminocarbonyl-L-valine benzyl ester (1.17 g). the mixture was concentrated under reduced pressure the residue was extracted with ethyl acetate (10 ml) The extract was washed with 1N-hydrochloric acid (10 ml) and aqueous sodium bicarbonate (10 ml) concentrated to dryness

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

Procedure: According to EP 1714963 4-Bromomethyl-2′-cyanobiphenyl is condensed with L-valinebenzylester tosylate to give (S)-N-[(2′-cyanobiphenyl-4-yl]methyl]-(L)-valine benzylester hydrochloride. (S)-N-cyanobiphenyl-4-yl]methyl]-(L)-valine benzylester on reaction with valerylchloride yields (S)-N-cyanobiphenyl-4-yl]methyl]-N-valeryl-(L)-valine benzylester further by the reaction of tributyltin chloride and sodiumazide gives benzyl valsartan and debenzylation with Pd/C to give valsartan. Also discloses the process for the recovery of benzyl valsartan substantially free of organo tin impurity.

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

Procedure: According to EP 1714963 4-Bromomethyl-2′-cyanobiphenyl is condensed with L-valinebenzylester tosylate to give (S)-N-[(2′-cyanobiphenyl-4-yl]methyl]-(L)-valine benzylester hydrochloride. (S)-N-cyanobiphenyl-4-yl]methyl]-(L)-valine benzylester on reaction with valerylchloride yields (S)-N-cyanobiphenyl-4-yl]methyl]-N-valeryl-(L)-valine benzylester further by the reaction of tributyltin chloride and sodiumazide gives benzyl valsartan and debenzylation with Pd/C to give valsartan. Also discloses the process for the recovery of benzyl valsartan substantially free of organo tin impurity.

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

Procedure: To a solution of L-valine benzylester in MeOH (12 mL) was slowly added 1,3-propanesultone (604 mg, 5.0 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with cold MeOH and acetone (2×25 mL). It was dried in the vacuum oven (50° C.), affording the title compound (649 mg, 39%). 1H NMR (D2O, 500 MHz) δ ppm 7.47 (m, 5H), 5.41 (d, 1H, J=11.7 Hz), 5.31 (d, 3H, J=11.7 Hz), 4.04 (m, 1H), 3.19 (m, 2H), 2.95 (t, 2H, J=6.8 Hz), 2.35 (m, 1H), 2.14 (m, 2H), 1.04 (d, 3H, J=6.3 Hz), 0.95 (d, 3H, J=6.3 Hz). 13C (D2O, 125 MHz) δ ppm 168.75, 134.81, 129.38, 129.31, 129.17, 69.00, 65.96, 48.24, 46.71, 29.67, 21.40, 18.39, 16.65. [α]D=−7.2° (c=0.0015 in water), ES-MS 330 (M+1). at reflux for 2 hours The solid was collected by filtration washed with cold MeOH and acetone (2×25 mL) It was dried in the vacuum oven (50° C.)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 44 g BocGlyOH (0.25 moles) is dissolved in 250 ml DMF, together with 29 g HOSu. After cooling to -20° C. 52 g DCC dissolved in 250 ml DMF is added. After 4 hours stirring at room temperature 95 g ValOBzl, pTos is added together with 35 ml TEA. After stirring overnight at room temperature, DCU is filtered off, DMF removed and the resulting oil taken up in EtAc and washed with sat. NaCl, sat. NaHCO, and 10% citric acid. The EtAc is dried with Na2SO4, removed by vacuum evaporation and the resulting crystalline mass dried in a desiccator. Yield: 59 g (65%). is added DCU is filtered off DMF removed washed with sat. NaCl, sat. NaHCO, and 10% citric acid The EtAc is dried with Na2SO4 removed by vacuum evaporation the resulting crystalline mass dried in a desiccator

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 44 g BocGlyOH (0.25 moles) is dissolved in 250 ml DMF, together with 29 g HOSu. After cooling to -20° C. 52 g DCC dissolved in 250 ml DMF is added. After 4 hours stirring at room temperature 95 g ValOBzl, pTos is added together with 35 ml TEA. After stirring overnight at room temperature, DCU is filtered off, DMF removed and the resulting oil taken up in EtAc and washed with sat. NaCl, sat. NaHCO, and 10% citric acid. The EtAc is dried with Na2SO4, removed by vacuum evaporation and the resulting crystalline mass dried in a desiccator. Yield: 59 g (65%). is added DCU is filtered off DMF removed washed with sat. NaCl, sat. NaHCO, and 10% citric acid The EtAc is dried with Na2SO4 removed by vacuum evaporation the resulting crystalline mass dried in a desiccator

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

Procedure: 15.83 g of 1-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate and 9 ml of N-methylmorpholine were added to a solution of 13.65 g of Z-Asp(OBut)-OH.H2O and 15.9 g of Val-OBzl.TosOH in 250 ml of DMF. After stirring for 2 hours the reaction mixture was evaporated in a vacuum and the residue was partitioned between ethyl acetate and water. The organic phase was washed with 5% KHSO4 /10% K2SO4 solution, water, saturated NaHCO3 solution, water and saturated NaCl solution, dried over Na2SO4, filtered and evaporated. The residue was crystallized from diethyl ether/hexane and there were obtained 17.5 g of Z-Asp(OBut)-Val-OBzl of m.p. 99°; [a]D20 -27.7° (c=1, MeOH). was evaporated in a vacuum the residue was partitioned between ethyl acetate and water The organic phase was washed with 5% KHSO4 /10% K2SO4 solution, water, saturated NaHCO3 solution, water and saturated NaCl solution dried over Na2SO4 filtered evaporated The residue was crystallized from diethyl ether/hexane

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

Procedure: 15.83 g of 1-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate and 9 ml of N-methylmorpholine were added to a solution of 13.65 g of Z-Asp(OBut)-OH.H2O and 15.9 g of Val-OBzl.TosOH in 250 ml of DMF. After stirring for 2 hours the reaction mixture was evaporated in a vacuum and the residue was partitioned between ethyl acetate and water. The organic phase was washed with 5% KHSO4 10% K2SO4 solution, water, saturated NaHCO3 solution, water and saturated NaCl solution, dried over Na2SO4, filtered and evaporated. The residue was crystallized from diethyl ether/hexane and there were obtained 17.5 g of Z-Asp(OBut)-Val-OBzl of m.p. 99°; [α]D20 -27.7° (c=1, MeOH). was evaporated in a vacuum the residue was partitioned between ethyl acetate and water The organic phase was washed with 5% KHSO4 10% K2SO4 solution, water, saturated NaHCO3 solution, water and saturated NaCl solution dried over Na2SO4 filtered evaporated The residue was crystallized from diethyl ether/hexane

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

Procedure: 15.83 g of 1-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate and 9 ml of N-methylmorpholine were added to a solution of 13.65 g of Z-Asp(OBut)-OH.H2O and 15.9 g of Val-OBzl.TosOH in 250 ml of DMF. After stirring for 2 hours the reaction mixture was evaporated in a vacuum and the residue was partitioned between ethyl acetate and water. The organic phase was washed with 5% KHSO4 10% K2SO4 solution, water, saturated NaHCO3 solution, water and saturated NaCl solution, dried over Na2SO4, filtered and evaporated. The residue was crystallized from diethyl ether/hexane and there were obtained 17.5 g of Z-Asp(OBut)-Val-OBzl of m.p. 99°; [α]D20 -27.7° (c=1, MeOH). was evaporated in a vacuum the residue was partitioned between ethyl acetate and water The organic phase was washed with 5% KHSO4 10% K2SO4 solution, water, saturated NaHCO3 solution, water and saturated NaCl solution dried over Na2SO4 filtered evaporated The residue was crystallized from diethyl ether/hexane