| 85% |
With hydrogen bromide; potassium bromide; sodium nitrite In water at -13 - 20℃; for 20h; |
|
| 84% |
With potassium hydroxide; hydrogen bromide; sodium nitrite In water; toluene |
Preparation of R-2-bromo-3-phenylpropionic Acid
Preparation of R-2-bromo-3-phenylpropionic Acid 46.0 ml water was supplied to a 1-litre double-walled glass reactor connected to a coolant. 275.5 g HBr 48% was added. Jacket cooling and stirring were started. Subsequently 67.7 gram KOH 45% was slowly added. The reaction mixture was cooled to 30-40° C. 45.0 g D-phenylalanine was added to the reaction mixture. Subsequently 213 ml toluene was added to the reaction mixture. The reaction mixture was cooled to 3° C. 95.9 g 30% NaNO2 solution in water was metered into the reaction mixture in 6 hours. The temperature was kept at 5° C. After the reaction stirring was continued for 3 hours at 3° C. The reaction mixture was heated to 20° C. Stirring was stopped and the aqueous phase was separated off. Then the toluene phase was additionally extracted two times with 95 ml water. The reaction mixture was heated to 70° C. and with the aid of a vacuum pump it was brought under a 100 mbar vacuum. Using a Dean-Stark setup the water was distilled off until the toluene phase was water-free. Yield: 84.0% R-2-bromo-3-phenylpropionic acid in the toluene solution, relative to D-phenylalanine. |
| 84% |
With potassium hydroxide; hydrogen bromide In water; toluene; sodium nitrite |
I Preparation of R-2-bromo-3-phenylpropionic acid
EXAMPLE I Preparation of R-2-bromo-3-phenylpropionic acid 46.0 ml of water was introduced into a 1-litre double-walled glass reactor connected to a cooling medium. 275.5 g of 48% HBr was added. The jacket cooling and stirring were started. Subsequently, 67.7 g of 45% KOH was slowly added. The reaction mixture was cooled to 30-40° C. 45.0 g of D-phenylalanine was added to the reaction mixture. Next, 213 ml of toluene was added to the reaction mixture. The reaction mixture was cooled to 3° C. In 6 hours 95.9 g of NaNO2, a 30% solution in water, was added to the reaction mixture. The temperature was kept at 5° C. After the reaction stirring was continued for 3 hours at 3° C. The reaction mixture was heated to 20° C. Stirring was stopped and the aqueous phase was separated off. Then the toluene phase was extracted twice with 95 ml of water. The reaction mixture was heated to 70° C. and a 100 mbar vacuum was created using a vacuum pump. The water was removed by distillation using a Dean Stark apparatus until the toluene phase was free of water. Yield: 84.0% R-2-bromo-3-phenylpropionic acid in the toluene solution, relative to D-phenylalanine. |
| 80% |
With hydrogen bromide; sodium bromide; sodium nitrite for 3h; Ambient temperature; |
|
| 67% |
With sulfuric acid; sodium bromide; sodium nitrite In water at 0 - 20℃; |
General procedure for manual bromination of amino acid
General procedure: To a solution of amino acid (1.00 equiv.) and 30% sodium bromide aq. (1.30 mL/mmol) were added 25% sulfuric acid aq. (1.30 mL/mmol) and 20% sodium nitrite aq. (0.650 mL/mmol) at 0 oC. After being stirred at the same temperature for 6 h, the aqueous layer was extracted with two portions of ethyl acetate. The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (100% ethyl acetate) to give bromocarboxylic acid. |
| 65% |
With sulfuric acid; potassium bromide; sodium nitrite 1) 0 deg C, 2 h, 2) r.t., 2 h; |
|
| 60% |
With hydrogen bromide; sodium nitrite In water |
1 (R)-2-Bromo-3-phenylpropanoic Acid
EXAMPLE 1 (R)-2-Bromo-3-phenylpropanoic Acid Sodium nitrite (27 g in water) is added at 0° C. to a solution of D-phenylalanine (40 g) in a mixture of 48% hydrobromic acid/water (1:1 by volume). The mixture is stirred for 30 minutes at 0° C. and then for 2 hours 30 minutes at a temperature close to 0° C. The reaction mixture is extracted with ether. The organic extracts are washed with water and a saturated sodium chloride solution and then dried over sodium sulphate. After filtration and concentration to dryness, the obtained residue is purified by distillation. (R)-2-Bromo-3-phenylpropanoic acid (33 g) is obtained which has the following characteristics: B.p.1kPa =154° C.; Rf =0.47 (methylene chloride/methanol). The yield is 60%. |
| 60% |
With hydrogen bromide; sodium nitrite In water |
A (R)-2-Bromo-3-phenylpropanoic Acid
EXAMPLE A (R)-2-Bromo-3-phenylpropanoic Acid Sodium nitrite (27 g in water) is added at 0°C to a solution of D-phenylalanine (40 g) in a mixture of 48% hydrobromic acid/water (1:1 by volume). The mixture is stirred for 30 minutes at 0°C and then for 2 hours 30 minutes at a temperature close to 20°C. The reaction mixture is extracted with ether. The organic extracts are washed with water and then with a saturated sodium chloride solution and then dried over sodium sulphate. After filtration and concentration to dryness, the obtained residue is purified by distillation. (R)-2-Bromo-3-phenylpropanoic acid (33 g) is obtained which has the following characteristics: B.p.1 kPa= 154°C; Rf= 0.47 (methylene chloride/methanol). The yield is 60%. |
| 50% |
With sulfuric acid; potassium bromide; sodium nitrite In water at -10 - 5℃; for 2h; |
1.1.1.1 1.1.1 Step 1: Synthesis of (R)-2-Bromo Carboxylic Acids
General procedure: The amino acid of configuration (R)- (39.3 mmol) is solubilized in 50 ml of water. At 0° C., KBr (3.5 eq, 31.8 g) and then H2SO4 (7.73 ml), respectively, are added dropwise, while maintaining the temperature below 5° C. The mixture is cooled to -10° C. and NaNO2 (1.3 eq, 3.59 g) solubilized in 17 ml of water is added dropwise. The mixture is stirred for 2 hours at -5° C. (0196) After returning to room temperature, the mixture is extracted with CH2Cl2 (2×50 ml). The organic phase is washed with H2O, saturated NaCl, dried on Na2SO4 to yield the expected product of configuration (R). (0197) 3a R2=CH2Ph: light yellow oil; (Yield: 50%); Rf (CH2Cl2/MeOH): 0.62 (0198) NMR (CDCl3, 200 MHz): 3.15-3.40 (2H, dd); 4.69 (1H, m); 7.20-7.40 (5H, m) |
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With sulfuric acid; potassium bromide; sodium nitrite |
|
| 12.7 g |
With sulfuric acid; potassium bromide; sodium nitrite for 1h; Ambient temperature; |
|
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With potassium bromide; sodium nitrite In sulfuric acid at 0℃; for 1h; |
|
|
With sulfuric acid; sodium bromide; sodium nitrite |
|
|
With hydrogen bromide; potassium bromide; sodium nitrite |
|
|
With sulfuric acid; potassium bromide; sodium nitrite In water |
|
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Stage #1: D-(R)-phenylalanine With hydrogen bromide In water at 0℃; for 0.166667h;
Stage #2: With sodium nitrite In water at 0 - 20℃; for 3.5h; |
4.1.2.1. 2-Bromo-4-(methylthio)butanoic acid (35c).
General procedure: To a solution ofDL-methionine (3.0 g, 20.1 mmol) in H2O (50 mL) was added 30% HBr (20 mL). The reaction mixture was stirred at 0 C for 10 min. A solution of sodium nitrite (1.7 g, 24 mmol) in H2O (50 mL) was added. The reaction mixture was stirred at 0 C for 30 min and thenwarmed to rt for 3 h. The reaction mixture was extracted withEtOAc (100 mL 3). The organic layer was washed with brine and dried over Na2SO4. The solid was filtered off, and the filtrate was concentrated under reduced pressure to give 3.6 g of intermediate 35c (83% yield). |
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