methyl (2R)-2-amino-3-phenylpropanoate

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

Procedure: To 310 parts by volume of an aqueous 0.5N sodium hydroxide solution, heated to about 70°, is added, successively, 17.7 parts of N-acetyl-L-phenylalanine and 33.3 parts of DL-phenylalanine methyl ester hydrochloride. A precipitate forms and upon cooling and filtering, the salt of N-acetyl-L-phenylalanine and D-phenylalanine methyl ester is obtained. Recrystallization from hot water affords the pure salt exhibiting an [α]D in 0.5% water of about +32.2°. is added A precipitate forms and upon cooling filtering

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

Procedure: To 310 parts by volume of an aqueous 0.5N sodium hydroxide solution, heated to about 70°, is added, successively, 17.7 parts of N-acetyl-L-phenylalanine and 33.3 parts of DL-phenylalanine methyl ester hydrochloride. A precipitate forms and upon cooling and filtering, the salt of N-acetyl-L-phenylalanine and D-phenylalanine methyl ester is obtained. Recrystallization from hot water affords the pure salt exhibiting an [α]D in 0.5% water of about +32.2°. is added A precipitate forms and upon cooling filtering

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

Procedure: 5.0 Parts of D-phenylalanine methyl ester, dissolved in 80 parts of methanol, is treated, at room temperature, with 0.90 part of sodium methoxide. The mixture is heated rapidly to reflux and maintained at reflux for about 21/21/2 hours. Then the reaction mixture is cooled, acidified to pH 2 with concentrated hydrochloric acid and evaporated to dryness. The remaining crystalline residue is taken up in water, and sodium carbonate is added. 1,2-Dichloroethane is added to form two phases and the mixture is shaken and filtered. The organic layer is separated, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate is acidified with hydrochloric acid, cooled and stripped of solvent. Trituration with ether of the material which remains after solvent removal and subsequent filtration yields DL-phenylalanine methyl ester hydrochloride, melting at about 162°. The mixture is heated rapidly to reflux maintained at reflux for about 21/21/2 hours Then the reaction mixture is cooled evaporated to dryness sodium carbonate is added 1,2-Dichloroethane is added to form two phases filtered The organic layer is separated washed with saturated sodium chloride solution dried over anhydrous magnesium sulfate filtered cooled after solvent removal and subsequent filtration

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

Procedure: 5.0 Parts of D-phenylalanine methyl ester, dissolved in 80 parts of methanol, is treated, at room temperature, with 0.90 part of sodium methoxide. The mixture is heated rapidly to reflux and maintained at reflux for about 21/21/2 hours. Then the reaction mixture is cooled, acidified to pH 2 with concentrated hydrochloric acid and evaporated to dryness. The remaining crystalline residue is taken up in water, and sodium carbonate is added. 1,2-Dichloroethane is added to form two phases and the mixture is shaken and filtered. The organic layer is separated, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate is acidified with hydrochloric acid, cooled and stripped of solvent. Trituration with ether of the material which remains after solvent removal and subsequent filtration yields DL-phenylalanine methyl ester hydrochloride, melting at about 162°. The mixture is heated rapidly to reflux maintained at reflux for about 21/21/2 hours Then the reaction mixture is cooled evaporated to dryness sodium carbonate is added 1,2-Dichloroethane is added to form two phases filtered The organic layer is separated washed with saturated sodium chloride solution dried over anhydrous magnesium sulfate filtered cooled after solvent removal and subsequent filtration

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

Procedure: Example 17 was repeated except for using DL-phenylalanine methyl ester instead of L-phenylalanine methyl ester to obtain 756 mg of an addition compound of N-benzyloxycarbonyl-L-aspartyl L-phenylalanine methyl ester and D-phenyl alanine methyl ester (1:1) (melting point: 105 to 111° C; yield: 62.3% based on N-benzyloxycarbonyl L-aspartic acid).

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

Procedure: Example 17 was repeated except for using DL-phenylalanine methyl ester instead of L-phenylalanine methyl ester to obtain 756 mg of an addition compound of N-benzyloxycarbonyl-L-aspartyl L-phenylalanine methyl ester and D-phenyl alanine methyl ester (1:1) (melting point: 105 to 111° C; yield: 62.3% based on N-benzyloxycarbonyl L-aspartic acid).

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

Procedure: Compound 40 (340 mg, 0.785 mmol) and D-phenylalanine methyl ester (HCl salt, 339 mg, 1.57 mmol) were subjected to a procedure similar to that described in Example 6. Flash chromatography (SiO2, 5:2:0.25 CHCl3/MeOH/H2O containing 0.5% conc. NH4OH) gave the title compound (282 mg, 68%) as a white solid. 1H NMR (D2O, 300 MHz) 7.415 (s, 1H), 7.1580-6.998 (m, 5H), 5.995 (t, J=6.8 Hz, 1H), 4.118 (m, 1H), 3.808 (m, 1H), 3.738 (m, 1H), 3.661 (m, 1H), 3.467 (m, 1H), 3.403 (s, 3H), 2.754 (m, 2H), 2.212 (m, 2H), 1.679 (s, 3H); 31P NMR (D2O, 121 MHz) 6.204; HRMS (FAB) m/z calcd for C13H20N6O8P (M+H)+ 419.1080, found 419.1103.

Conditions: temp:2.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An aqueous solution of 153.2 mmol of D-phenylalanine methyl ester and 4.6 mmol of L-phenylalanine methyl ester (D/L ratio=97.1/2.9) and 335 mmol of HCl in 400 ml of pure water was neutralized to pH 3 with a 20% NaOH aqueous solution and concentrated to a weight of 100 g by means of a rotary evaporator. The concentrate was cooled to about 2° C., and the precipitated crystals were collected by filtration by suction. There was obtained 120.7 mmol of D-phenylalanine methyl ester hydrochloride having an optical purity of 99.97% as measured by HPLC. concentrated to a weight of 100 g by means of a rotary evaporator the precipitated crystals were collected by filtration by suction

Conditions: temp:2.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An aqueous solution of 153.2 mmol of D-phenylalanine methyl ester and 4.6 mmol of L-phenylalanine methyl ester (D/L ratio=97.1/2.9) and 335 mmol of HCl in 400 ml of pure water was neutralized to pH 3 with a 20% NaOH aqueous solution and concentrated to a weight of 100 g by means of a rotary evaporator. The concentrate was cooled to about 2° C., and the precipitated crystals were collected by filtration by suction. There was obtained 120.7 mmol of D-phenylalanine methyl ester hydrochloride having an optical purity of 99.97% as measured by HPLC. concentrated to a weight of 100 g by means of a rotary evaporator the precipitated crystals were collected by filtration by suction

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

Procedure: (2R)-2-Amino-3-phenylpropionic acid methyl ester (3.2 g; 15.0 mmol) and (2-oxoethyl)carbamic acid tert-butyl ester (3.2 g; 20.0 mmol) (prepared as in Dueholm et al, Org. Prep. Proced. Int. 25(4), 457-61 (1993)) were dissolved in a mixture of methanol (100 ml) and acetic acid (5 ml). Molecular sieves (3 Å; 100 g) were added and the reaction mixture was cooled to 0° C. Sodium cyanoborohydride (1.38 g; 22.0 mmol) was added portionwise and the reaction mixture was left without stirring for 12 h. The reaction mixture was filtered and water (100 ml), aqueous sodium hydrogencarbonate/sodium carbonate (10%; 100 ml; pH 9) and methylene chloride (50 ml) were added to the filtrate. The aqueous phase was extracted with methylene chloride (2×50 ml) and the combined organic phases were dried over magnesium sulfate. The organic phase was evaporated in vacuo and the residue was chromatographed on silica (4×40 cm) using ethyl acetate/heptane (3:2) as eluent to afford 2.07 g of (2R)-2-(2-(tert-butoxycarbonylamino)ethylamino)-3-phenylpropionic acid methyl ester. Molecular sieves (3 Å; 100 g) were added the reaction mixture was left The reaction mixture was filtered water (100 ml), aqueous sodium hydrogencarbonate/sodium carbonate (10%; 100 ml; pH 9) and methylene chloride (50 ml) were added to the filtrate The aqueous phase was extracted with methylene chloride (2×50 ml) the combined organic phases were dried over magnesium sulfate The organic phase was evaporated in vacuo the residue was chromatographed on silica (4×40 cm)

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

Procedure: (2R)-2-Amino-3-phenylpropionic acid methyl ester (3.2 g; 15.0 mmol) and (2-oxoethyl)carbamic acid tert-butyl ester (3.2 g; 20.0 mmol) (prepared as in Dueholm et al, Org. Prep. Proced. Int. 25(4), 457-61 (1993)) were dissolved in a mixture of methanol (100 ml) and acetic acid (5 ml). Molecular sieves (3 Å; 100 g) were added and the reaction mixture was cooled to 0° C. Sodium cyanoborohydride (1.38 g; 22.0 mmol) was added portionwise and the reaction mixture was left without stirring for 12 h. The reaction mixture was filtered and water (100 ml), aqueous sodium hydrogencarbonate/sodium carbonate (10%; 100 ml; pH 9) and methylene chloride (50 ml) were added to the filtrate. The aqueous phase was extracted with methylene chloride (2×50 ml) and the combined organic phases were dried over magnesium sulfate. The organic phase was evaporated in vacuo and the residue was chromatographed on silica (4×40 cm) using ethyl acetate/heptane (3:2) as eluent to afford 2.07 g of (2R)-2-(2-(tert-butoxycarbonylamino)ethylamino)-3-phenylpropionic acid methyl ester. Molecular sieves (3 Å; 100 g) were added the reaction mixture was left The reaction mixture was filtered water (100 ml), aqueous sodium hydrogencarbonate/sodium carbonate (10%; 100 ml; pH 9) and methylene chloride (50 ml) were added to the filtrate The aqueous phase was extracted with methylene chloride (2×50 ml) the combined organic phases were dried over magnesium sulfate The organic phase was evaporated in vacuo the residue was chromatographed on silica (4×40 cm)

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

Procedure: To 1.0 mmol alcohol 2b dissolved in 10 mL acetone at 0° C. was added 1.5 mmol H2Cr2O7 (3 mL Jones reagent). The mixture was stirred for 5 h, during which time the mixture warmed to room temperature. Excess isopropanol was added, and the mixture was stirred for 10 min. The mixture was filtered, and the solution was diluted with 2 mL 2 N HCl and extracted with Et2O. Complete extraction of the product into the Et2O phase was monitored by TLC. The organic layers was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give a viscous oil, of which the desired product 3 was purified via column chromatography eluting with EtOAc/hexane (1:10 to 1:3; v/v) to give pure product as a yellow oil in 92% yield. TLC Rf=0.45 (EtOAc/hexanes, v/v, 1:1) 1H NMR (300 MHz, CDCl3) 4.56-4.41 (m, 2H), 2.53-2.44 (m, 1H), 2.38-2.19 (m, 2H), 1.84-1.60 (m, 2H), 1.00 (t, J=7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 180.66, 73.55, 43.57, 28.41, 25.24, 11.41. HRMS m/z (ESI): calc. for C6H11NO4Na [M+Na]+184.0586, found 184.0578. Optical rotation: [α]rtD+17.51 (c=3.82, CHCl3). The ee of this compound (>95%) was determined by coupling one portion to L-Phe-OMe and another portion to D-Phe-OMe and then analyzing the products by 1H NMR spectroscopy. the mixture was stirred for 10 min The mixture was filtered the solution was diluted with 2 mL 2 N HCl extracted with Et2O extraction of the product into the Et2O phase The organic layers was washed with saturated NaCl dried over MgSO4 filtered concentrated to give a viscous oil of which the desired product 3 was purified via column chromatography eluting with EtOAc/hexane (1:10 to 1:3; v/v) to give pure product as a yellow oil in 92% yield