O-Benzyl-L-tyrosine

Crystalline

Tyrosine (7.25 g, 40 mmol) was dissolved in an aqueous solution of sodium hydroxide (2 mol/L, 20 mL). The resulting solution was stirred for 15 min at rt, and then warmed to 70 °C. A solution of CuSOTyrosine (7.25 g, 40 mmol) was dissolved in an aqueous solution of sodium hydroxide (2 mol/L, 20 mL). The resulting solution was stirred for 15 min at rt, and then warmed to 70 °C. A solution of CuSOIn a 5 Liter three necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, L-tyrosine (100 g), sodium hydroxide (24.28 g) solution in water (276 ml) and cupric sulfate pentahydrate (82.6 g) solution in water (276 ml) were added at room temperature. The reaction mixture was heated to reflux temperature for 1 hour and cooled to 20° to 30°C. Methanol (1990 mL) was added and subsequently sodium hydroxide (24.28 g) solution in water (276 ml) and benzyl bromide solution (113.2 g) were added. The reaction mixture was heated to 60°C-65°C and maintained for 4 hours and cooled to 20° to 30°C. The reaction mixture was filtered and washed with water-methanol mixture (1 :2) and dried for 30 min. The wet-cake was treated with HCl solution (162.0 ml) in water (944 ml) and resulting reaction mixture was cooled to 15° to 20°C and stirred for 30 min. The reaction mixture was filtered and washed with water. The wet-cake was treated with aqueous liquor ammonia solution (1 105 ml) and stirred for 1 hour. The product was filtered and washed with water and dried to obtain 1 10 g of compound (D).To an ice cooled solution of potassium hydroxide (40.0 g, 0.605 mol) in 100 ml of water was added L-tyrosine (50 g, 0.275 mol) portion wise with maintaining inner temperature at 15-20 Example; Preparation of O-Benzyl-L-Tyrosine; In a dry, 50 L glass assembly was charged water (6L) and potassium hydroxide pellets (2.409 kg, 36.56 mol) and cooled to CA. 26-28 C. To this solution L-tyrosine (3 kg, 16.57 mol) and copper sulfate pentahydrate (2.565 kg, 10.3 mol) was added at ca. 26-28 °C with stirring. The mixture was heated to 60 °C-65 °C with stirring and cooled. DMF (12 L) was added to it. Benzyl chloride (2.516 kg, 19.88 mol) was added slowly between 50 °C to 60 °C with stirring. Gray coloured solid copper complex of 0-benzyl-L-tyrosine precipitates out. The mixture was cooled to ca. 26-28 °C, stirred and resulting solids were collected by filtration, washed with water and drained well under vacuum. The wet cake OF O-BENZYL-L-TYROSINE copper complex (18.2 kg) was stirred with methanol in a 50 L glass assembly at reflux temperature. The solids were filtered hot through filter cloth using nutch filter, drained well and washed with methanol. It was dried in an oven at 65 °C- 70 °C. The copper complex OF O-BENZYL-L-TYROSINE weighed about 4.6 kg. The Cu complex of 0-benzyl-L-tyrosine was added into water in a 30 lit S. S. tank. It was stirred at ca. 26-28 °C. To this slurry 35 percent conc. HCl (3.32 L) was added with stirring, and the solids obtained were filtered and drained well followed by washing with water and 10 percent ammonia solution. The wet cake was centrifuged and again washed with water. The solids were dried in an oven at 65 °C-70 °C. The off white 0-benzyl-L-tyrosine was obtained in 56 percent yield (2. 63 kg) with 95.8 percent assay by HPLC and 100 percent e. e; Preparation of O-Benzyl-L-Tyrosine; In a dry 100 L glass assembly was charged water (10 L) and potassium hydroxide pellets (4 kg, 71.5 mol) and cooled to room temperature. To this solution L-tyrosine (5 kg, 27.62 mol) and copper sulfate PENTAHYDRATE (4.3 kg, 17.17 mol) was added at ca 26-28 °C with stirring. The mixture was heated to 60 °C-65 °C with stirring and cooled. DMF (20 L) was added to it. Benzyl chloride (4.2 kg, 33.14 mol) was added slowly between 50 °C to 60 °C with stirring. Gray coloured solid copper complex of 0-benzyl-L-tyrosine precipitates out. The mixture was cooled to ca 26-28 °C, stirred, and resulting solids were collected by filtration, washed with water and drained well under vacuum. The wet cake of 0-benzyl-L-tyrosine copper complex (25.6 kg) was stirred with methanol in a 100 L glass assembly at reflux temperature. The solids were filtered hot through filter cloth using nutch filter, drained well and washed with methanol. It was dried in an oven at 65 °C- 70 °C. The copper complex of 0-benzyl-L-tyrosine weighed about 8.2 kg. The Cu complex of 0-benzyl-L-tyrosine was added into water in a 50 lit S. S. tank and stirred at ca 26-28 °C. To this slurry 35 percent conc. HCl (5.8 L) was added with stirring, the solids obtained were filtered, drained well followed by washing with water and 10 percent ammonia solution. The wet cake was centrifuged and again was washed with water. The solids were dried in an oven at 65 °C-70 °C. The off white 0-benzyl-L-tyrosine was obtained in 54.7 percent yield (4.3 kg) with 95 percent assay by HPLC and 100 percent e. ES (-) 2-hydroxy-3- (4-benzyloxyphenyl) propanoic acid; To a 2 L round bottom three necked flask, 1, 4 dioxane (625 mL) was added followed by O- benzyl-L-tyrosine (50 g, 0.184 mol). To this suspension dilute aqueous sulfuric acid solution (54 g, 0.553 mol, in 175 mL water) was added at ca 26-28 C. It was cooled to 0 C-2 C in an ice salt BATH.. At 0 C, aqueous sodium nitrite solution (63.6 g, 0.922 mol) was added dropwise. After the addition, it was stirred for an extended period of time (-UPTO 24 hours) below 30 C. It was diluted with water and extracted with ethyl acetate. Extracts were combined and washed with water. Organic layer was collected and dried over anhydrous sodium sulfate. It was filtered and filtrate was concentrated below 45 C to dryness under reduced pressure to obtain crude semi-solid product (58.9 g). The crude product was purified by stirring in a mixture of diisopropyl ether & ethyl acetate and filtered and washed with diisopropyl ether. The product obtained was dried in an oven at 55 C-60 C. The product weighs about 25.7 g (51 % yield). The IHPLC assay was 92.3 % and enatiomeric excess was 100 %; Example 8; S (-) 2-hydroxy-3- (4-benzyloxyphenyl) propanoic acid; To a 20 L round bottom three necked flask, 1, 4 dioxane (6.25 L) was added followed by 0- benzyl-L-tyrosine (500G, 1.84 mol). To this suspension dilute aqueous sulfuric acid solution (540 G, 5. 53 mol, in 2.5 L water) was added at RT. It was cooled to 0 C-2 C in an ice salt bath. At 0 C, aqueous sodium nitrite solution (636 g, 9.22 mol) was added. After the addition, it was stirred for extended period of time (-UPTO 24 hours) below 30 C. It was diluted with water and extracted with ethyl acetate. Extracts were combined and washed with water. Organic layer was collected and dried over anhydrous sodium sulfate. It was filtered and filtrate was concentrated below 45 C to dryness under reduced pressure to obtain crude semi-solid product (820 g). The crude product was purified by stirring in a mixture of diisopropyl ether & ethyl acetate. It was filtered and washed with diisopropyl ether. The dark yellowish product obtained was dried in an oven at 55 C-60 C. The product weighs about 235 g (47 % yield). The HPLC assay was 98.4 % and enatiomeric excess was 98 %S (-) 2-hydroxy-3- (4-benzyloxyphenyl) propanoic acid; To a 2 L round bottom three necked flask, 1, 4 dioxane (625 mL) was added followed by O- benzyl-L-tyrosine (50 g, 0.184 mol). To this suspension dilute aqueous sulfuric acid solution (54 g, 0.553 mol, in 175 mL water) was added at ca 26-28 C. It was cooled to 0 C-2 C in an ice salt BATH.. At 0 C, aqueous sodium nitrite solution (63.6 g, 0.922 mol) was added dropwise. After the addition, it was stirred for an extended period of time (-UPTO 24 hours) below 30 C. It was diluted with water and extracted with ethyl acetate. Extracts were combined and washed with water. Organic layer was collected and dried over anhydrous sodium sulfate. It was filtered and filtrate was concentrated below 45 C to dryness under reduced pressure to obtain crude semi-solid product (58.9 g). The crude product was purified by stirring in a mixture of diisopropyl ether & ethyl acetate and filtered and washed with diisopropyl ether. The product obtained was dried in an oven at 55 C-60 C. The product weighs about 25.7 g (51 % yield). The IHPLC assay was 92.3 % and enatiomeric excess was 100 %; Example 8; S (-) 2-hydroxy-3- (4-benzyloxyphenyl) propanoic acid; To a 20 L round bottom three necked flask, 1, 4 dioxane (6.25 L) was added followed by 0- benzyl-L-tyrosine (500G, 1.84 mol). To this suspension dilute aqueous sulfuric acid solution (540 G, 5. 53 mol, in 2.5 L water) was added at RT. It was cooled to 0 C-2 C in an ice salt bath. At 0 C, aqueous sodium nitrite solution (636 g, 9.22 mol) was added. After the addition, it was stirred for extended period of time (-UPTO 24 hours) below 30 C. It was diluted with water and extracted with ethyl acetate. Extracts were combined and washed with water. Organic layer was collected and dried over anhydrous sodium sulfate. It was filtered and filtrate was concentrated below 45 C to dryness under reduced pressure to obtain crude semi-solid product (820 g). The crude product was purified by stirring in a mixture of diisopropyl ether & ethyl acetate. It was filtered and washed with diisopropyl ether. The dark yellowish product obtained was dried in an oven at 55 C-60 C. The product weighs about 235 g (47 % yield). The HPLC assay was 98.4 % and enatiomeric excess was 98 %S (-) 2-hydroxy-3- (4-benzyloxyphenyl) propanoic acid; To a 2 L round bottom three necked flask, 1, 4 dioxane (625 mL) was added followed by O- benzyl-L-tyrosine (50 g, 0.184 mol). To this suspension dilute aqueous sulfuric acid solution (54 g, 0.553 mol, in 175 mL water) was added at ca 26-28 C. It was cooled to 0 C-2 C in an ice salt BATH.. At 0 C, aqueous sodium nitrite solution (63.6 g, 0.922 mol) was added dropwise. After the addition, it was stirred for an extended period of time (-UPTO 24 hours) below 30 C. It was diluted with water and extracted with ethyl acetate. Extracts were combined and washed with water. Organic layer was collected and dried over anhydrous sodium sulfate. It was filtered and filtrate was concentrated below 45 C to dryness under reduced pressure to obtain crude semi-solid product (58.9 g). The crude product was purified by stirring in a mixture of diisopropyl ether & ethyl acetate and filtered and washed with diisopropyl ether. The product obtained was dried in an oven at 55 C-60 C. The product weighs about 25.7 g (51 % yield). The IHPLC assay was 92.3 % and enatiomeric excess was 100 %; Example 8; S (-) 2-hydroxy-3- (4-benzyloxyphenyl) propanoic acid; To a 20 L round bottom three necked flask, 1, 4 dioxane (6.25 L) was added followed by 0- benzyl-L-tyrosine (500G, 1.84 mol). To this suspension dilute aqueous sulfuric acid solution (540 G, 5. 53 mol, in 2.5 L water) was added at RT. It was cooled to 0 C-2 C in an ice salt bath. At 0 C, aqueous sodium nitrite solution (636 g, 9.22 mol) was added. After the addition, it was stirred for extended period of time (-UPTO 24 hours) below 30 C. It was diluted with water and extracted with ethyl acetate. Extracts were combined and washed with water. Organic layer was collected and dried over anhydrous sodium sulfate. It was filtered and filtrate was concentrated below 45 C to dryness under reduced pressure to obtain crude semi-solid product (820 g). The crude product was purified by stirring in a mixture of diisopropyl ether & ethyl acetate. It was filtered and washed with diisopropyl ether. The dark yellowish product obtained was dried in an oven at 55 C-60 C. The product weighs about 235 g (47 % yield). The HPLC assay was 98.4 % and enatiomeric excess was 98 %To a stirred suspension of (2S)-2-amino-3-(4-benzyloxyphenyl)propionic acid (45 g, 0.166 mol) in 565 ml of 1, 4-dioxane was added dilute aqueous H2SO4 solution (48.62 g, 0.496 mol in 157.5 ml of water) at 25 0C. The resulted reaction mixture was cooled to 0 0C on ice bath and to this was added aqueous sodium nitrite solution (57.24 g, 0.826 mol in 80 ml of water) at 0 0C in a dropwise manner under stirring. After the completion of addition the reaction mixture was stirred at room temperature for 24 h. Reaction mixture was diluted with water (2000 ml), extracted with ethyl acetate (3x800 ml). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to yield crude product. The crude product was suspended in mixture of 100 ml of diisopropyl ether and 1 ml of ethyl acetate. Resulting solid was filtered, washed with diisopropyl ether (50 ml) and dried under vacuum to yield the title compound (16.8 g 37%). General procedure: The Boc-protected amino acid (1 mmol) was treated with TFA (3 mL) for 15 minutes. Afterevaporation the residue was dissolved in dioxane-water (1:1, 4 mL) and the flask wasplaced in an ice bath. tert-Butylnitrite (0.13 mL, 1.1 mmol) was added and stirring wasmaintained under nitrogen at room temperature for one hour. After pouring the reactionmixture onto celite and evaporation (50 Pa, 30 C) into a dry free-floating powder, separation was performed utilizing a CombiFlash Rf (Teledyne ISCO) automated flashchromatography apparatus by means of AcOH-MeOH-EtOAc (1:9:90) on a normal phasesilica column affording the pure a-hydroxy carboxylic acid in the yield specified in Table 1.HO-His(Bom)-OH and HO-Arg(Tos)-OH were isolated by adding water (30 mL) to thereaction mixture followed by freeze drying and HPLC purification.In a 5 Liter three necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, DMSO (650 ml) was charged with 100 g of compound (D) as obtained in example 1. The reaction mixture was added with H2S04 solution (48.0 g) in 400 ml water and stirred to get the clear solution. The reaction mixture was cooled to -5 to 0C and sodium nitrite solution were added subsequently and stirred for 2 hours. The reaction mixture was raised to 15C to 25C and stirred for 1 hour. Water 1000 ml and 1000 ml of ethyl acetate were added and reaction mixture was stirred for 1 hour and filtered and treated with 400 ml of ethyl acetate and allowed to settle. The separated aqueous layer was treated with 200 ml of ethyl acetate 500 ml of water. The organic layer was treated with 10% sodium chloride solution and allowed to settle. The organic layer was separated and charcoalized and dried over sodium sulfate. The reaction mixture was filtered and washed with 100 ml of ethyl acetate. The filtrate was distilled and residue was treated with 5ml of DMSO. The reaction mixture was heated to 60 to 65C and cooled to 5 to 10C and filtered. The product was washed with ethyl acetate and dried in hot air oven for 12 hours at 50 to 55C

Molecular Weight:271.31
XLogP3:-0.1
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:6
Exact Mass:271.12084340
Monoisotopic Mass:271.12084340
Topological Polar Surface Area:72.6
Heavy Atom Count:20
Complexity:294
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes