benzyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate

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

Procedure: By substituting L-tyrosine benzyl ester for the L-alanine benzyl ester in the procedure of Example 23, and then treating the product by the procedure of Examples 24 and 26, N-(4-methoxycarbonyl-2-methylbutanoyl)-L-tyrosine benzyl ester, N-(4-methoxycarbonyl-2-methylbutanoyl)-L-tyrosine, and N-(4-carboxy-2-,ethylbutanoyl)-L-tyrosine are obtained. are obtained

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

Procedure: By substituting L-tyrosine benzyl ester for the L-alanine benzyl ester in the procedure of Example 23, and then treating the product by the procedure of Examples 24 and 26, N-(4-methoxycarbonyl-2-methylbutanoyl)-L-tyrosine benzyl ester, N-(4-methoxycarbonyl-2-methylbutanoyl)-L-tyrosine, and N-(4-carboxy-2-,ethylbutanoyl)-L-tyrosine are obtained. are obtained

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

Procedure: Using the procedure described in Example 60, but starting with 2-acetylthiomethyl-3-(4-hydroxyphenyl)butanoic acid and tyrosine benzyl ester, N-[2-acetylthiomethyl-3-(4-hydroxyphenyl)-1-oxobutyl]tyrosine benzyl ester is obtained in a 78% yield in the form of a white solid, having the following characteristics: Rf =0.16 [hexane/ethyl acetate (65:35 by volume)].

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

Procedure: When epoxysuccinic acid mono m-methylbenzyl ester chloride which was prepared from m-methylbenzyl potassium epoxysuccinate (i.e. m-methylbenzyl potassium oxirane 2,3-dicarboxylate) in a manner as described in Example 46 was reacted with L-tyrosine benzyl ester in dichloromethane by the same method as described in Example 47, N-(3-m-methylbenzyloxycarbonyloxirane-2-carbonyl)-L-tyrosine benzyl ester(EP-148) was obtained as a colorless oil. Yield 61%. Mass: m/e 489 (M+). IRνfilm (cm-1): 3480 (amine, hydroxy), 1750 (ester, 1685, 1540 (amide), 897 (epoxide). NMR(CDCl3)δ: 2.30 (3H, s), 3.02 (2H, d, J=6 Hz), 3.21 (0.5H, d, J=2 Hz), 3.47 (0.5H, d, J=2 Hz), 3.60 (0.5H, d, J=2 Hz), 3.64 (0.5H, d, J=2 Hz), 4.75 (1H, m), 5.12 (4H, s), 6.35 (1H, b), 6.25-7.20 (8H, m), 7.30 (5H, s).

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

Procedure: When 0.65 g of epoxysuccinic acid monoallylester chloride which was prepared from 1.0 g of allyl potassium epoxysuccinate (i.e. allyl potassium oxirane 2,3-dicarboxylate) by treatment with oxalyl chloride in a manner as described in Example 46 was reacted with L-tyrosine benzyl ester in dichloromethane by the method as described in Example 46, N-(3-allyloxycarbonyloxirane-2-carbonyl)-L-tyrosine benzyl ester(EP-147) was obtained as a colorless oil. Yield 1.0 g (68%). Mass: m/e 425 (M+). IRνfilm (cm-1): 3480 (amine, hydroxy), 1755 (ester), 1685, 1525 (amide), 1625 (C=C), 895 (epoxide). NMR(CDCl3)δ: 2.98 (2H, d, J=6 Hz), 3.19 (0.5H, d, J=2 Hz), 3.43 (0.5H, d, J=2 Hz), 3.58 (0.5H, d, J=2 Hz), 3.61 (0.5H, d, J=2 Hz), 4.5-6.2 (6H, m), 5.08 (2H, d, J=3 Hz), 6.25-7.0 (4H, m), 7.25 (5H, s).

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

Procedure: By substituting L-tyrosine benzyl ester for the L-alanine benzyl ester in the procedure of Example 23, and then treating the product by the procedure of Examples 24 and 26, N-(4-methoxycarbonyl-2-methylbutanoyl)-L-tyrosine benzyl ester, N-(4-methoxycarbonyl-2-methylbutanoyl)-L-tyrosine, and N-(4-carboxy-2-,ethylbutanoyl)-L-tyrosine are obtained. are obtained

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

Procedure: Using the procedure described in Example 60, but starting with 2-acetylthiomethyl-3-(4-hydroxyphenyl)butanoic acid and tyrosine benzyl ester, N-[2-acetylthiomethyl-3-(4-hydroxyphenyl)-1-oxobutyl]tyrosine benzyl ester is obtained in a 78% yield in the form of a white solid, having the following characteristics: Rf =0.16 [hexane/ethyl acetate (65:35 by volume)].

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

Procedure: Using the procedure described in Example 60, but starting with 2-acetylthiomethyl-3-(4-hydroxyphenyl)butanoic acid and tyrosine benzyl ester, N-[2-acetylthiomethyl-3-(4-hydroxyphenyl)-1-oxobutyl]tyrosine benzyl ester is obtained in a 78% yield in the form of a white solid, having the following characteristics: Rf =0.16 [hexane/ethyl acetate (65:35 by volume)].

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

Procedure: The para-toluenesulfonic acid salt of tyrosine benzyl ester (5.05 g, 11.4 mmol) was dissolved in THF (50 mL) containing DIEA (2.18 mL, 12.5 mmol) and di-tert-butyidicarbonate (2.98 g, 13.7 mmol) was added in one portion. The reaction was stirred 1.5 h at room temperature. Volatiles were removed under reduced pressure and the residue was dissolved in Et2O (150 mL). The solution was washed successively with water (25 mL), 5% citric acid (25 mL) and 5% NaHCO3 (25 mL). After drying (MgSO4), the solvent was evaporated under reduced pressure and the residue dissolved in acetone (100 mL). Cesium carbonate (4.83 g, 14.8 mmol) and methyl bromoacetate (1.3 mL, 13.7 mmol) were added and the heterogeneous mixture was stirred overnight at room temperature. Solids were then removed by filtration (acetone for washings) and the filtrate evaporated. The residue was dissolved in Et2O (150 mL) and washed with water (25 mL) and brine (25 mL). After drying (MgSO4), the solution was concentrated and the residue purified by flash chromatography using 25-50% EtOAc/hexane as eluent. The fully protected tyrosine derivative was obtained as a colorless oil (3.61 g). was added in one portion Volatiles were removed under reduced pressure the residue was dissolved in Et2O (150 mL) The solution was washed successively with water (25 mL), 5% citric acid (25 mL) and 5% NaHCO3 (25 mL) After drying (MgSO4) the solvent was evaporated under reduced pressure the residue dissolved in acetone (100 mL) the heterogeneous mixture was stirred overnight at room temperature Solids were then removed by filtration (acetone for washings) the filtrate evaporated The residue was dissolved in Et2O (150 mL) washed with water (25 mL) and brine (25 mL) After drying (MgSO4) the solution was concentrated the residue purified by flash chromatography

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

Procedure: As illustrated by FIG. 5H, tyrosine benzyl ester 111 can be converted to N-acetyltyrosine benzyl ester (2) using acetic anhydride, with the hydroxy group of the tyrosine being transformed into the trifluoromethyl sufonyl derivative 113 by using phenyl bis[(trifluoromethyl)sulfonyl]amine. Compound 113 this can be coupled to vinyltributyltin in the presence of bis(triphenylphosphine)palladium dichloride and lithium chloride to give the 4-ethenylphenylalanine derivative 114. This product, on refluxing with catechol borane and further transesterification with pinanediol, gives p-boronoethyl-2-phenylalanine derivative 116. Catalytic hydrogenation affords 117, which can be further coupled to yield the desired peptide or peptidomimetic.

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

Procedure: Nα -Tert.-butoxycarbonyl-NG -nitro-L-arginine (1.60 g) and L-tyrosine benzyl ester p-toluenesulfonate (2.22 g) are dissolved in anhydrous chloroform (20 ml), and thereto are added triethylamine (1.40 ml) and further 1-methanesulfonyloxy-1,2,3-benzotriazole (1.05 g) and the mixture is stirred at room temperature for 20 hours. After the reaction, to the reaction mixture are added ethyl acetate and water. The ethyl acetate layer is separated, washed with water, a saturated aqueous sodium hydrogen carbonate, water, an aqueous citric acid solution and water in order and then dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off, and the resulting residue is dissolved in chloroform, subjected to chromatography by using silica gel (20 g) and eluted with chloroform to give amorphous powder of N-(Nα -tert.-butoxycarbonyl-NG -nitro-L-arginyl)-L-tyrosine benzyl ester (2.0 g). After the reaction The ethyl acetate layer is separated washed with water a saturated aqueous sodium hydrogen carbonate, water, an aqueous citric acid solution and water in order and then dried over anhydrous magnesium sulfate After drying the solvent is distilled off the resulting residue is dissolved in chloroform eluted with chloroform

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

Procedure: When epoxysuccinic acid mono m-methylbenzyl ester chloride which was prepared from m-methylbenzyl potassium epoxysuccinate (i.e. m-methylbenzyl potassium oxirane 2,3-dicarboxylate) in a manner as described in Example 46 was reacted with L-tyrosine benzyl ester in dichloromethane by the same method as described in Example 47, N-(3-m-methylbenzyloxycarbonyloxirane-2-carbonyl)-L-tyrosine benzyl ester(EP-148) was obtained as a colorless oil. Yield 61%. Mass: m/e 489 (M+). IRνfilm (cm-1): 3480 (amine, hydroxy), 1750 (ester, 1685, 1540 (amide), 897 (epoxide). NMR(CDCl3)δ: 2.30 (3H, s), 3.02 (2H, d, J=6 Hz), 3.21 (0.5H, d, J=2 Hz), 3.47 (0.5H, d, J=2 Hz), 3.60 (0.5H, d, J=2 Hz), 3.64 (0.5H, d, J=2 Hz), 4.75 (1H, m), 5.12 (4H, s), 6.35 (1H, b), 6.25-7.20 (8H, m), 7.30 (5H, s).