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EXAMPLE 17; Step 17A: Compound 17a; To 35. 11 g (150 mmol) of D-2, 4-dichlorophenylalanine in 700 mL of THF was added 150 mL (225 mmol) of a 15% succinic semialdehyde in water solution. The mixture was stirred for 1 hour at room temperature. Sodium triacetoxyborohydride (63.6 g, 300 mmol) was added in three portions and the mixture stirred for 10 hours. The solution was carefully decanted to leave solid 17a. Acetic anhydride (100 mL), 250 mL of THF and 250 mL of EtOAc were added and the reaction mixture was stirred vigorously. The mixture was heated to-50 C for two hours. The THF and EtOAc were removed ill vacuo and the residue poured slowly into 1 L of vigorously stirred water. White precipitate was formed, filtered, and dried to give 17b (31.5 g) as a white solid
To a suspension of <strong>[114872-98-9]D-2,4-dichlorophenylalanine</strong> (10.00 g) in methanol (100 ml) was added dropwise thionylchloride (9.39 ml). During the course of the addition a clear solution was formed and the reaction started to reflux. The reaction mixture was kept under reflux for 2 h. After cooling to room temperature the mixture was evaporated to dryness at 40 C. The crude product was triturated in diethyl ether, and the insoluble compound was filtered off, washed with diethyl ether, and finally dried in vacuo at room temperature over P2O5 overnight. The product was obtained in form of colorless needles.
With thionyl chloride; for 2h;Heating / reflux;
Synthesis of B-C Moieties: B-C Moiety 1: Intermediate A1): [Show Image] To a suspension of <strong>[114872-98-9]D-2,4-dichlorophenylalanine</strong> (10.00 g) in methanol (100 ml) was dropwise added thionylchloride (9.39 ml). During the course of the addition a clear solution was formed and the reaction started to reflux. The reaction mixture was kept under reflux for 2 h. After cooling to room temperature the mixture was evaporated to dryness at 40 C. The crude product was triturated in diethyl ether, and the insoluble compound was filtered off, washed with diethyl ether, and finally dried in vacuo at room temperature over P2O5 overnight. The product was obtained in form of colorless needles.
With thionyl chloride; for 2h;Heating / reflux;
Intermediate A3): [Show Image] To a suspension of <strong>[114872-98-9]D-2,4-dichlorophenylalanine</strong> (10.00 g) in methanol (100 ml) was added dropwise thionylchloride (9.39 ml). During the course of the addition a clear solution was formed and the reaction started to reflux. The reaction mixture was kept under reflux for 2 h. After cooling to room temperature the mixture was evaporated to dryness at 40C. The crude product was triturated in diethyl ether, and the insoluble compound was filtered off, washed with diethyl ether, and finally dried in vacuo at room temperature over P2O5 overnight. The product was obtained in form of colorless needles.
With thionyl chloride;Reflux;
To a suspension of <strong>[114872-98-9]D-2,4-dichlorophenylalanine</strong> (10.00 g) in methanol (100 ml) was dropwise added thionylchloride (9.39 ml). During the course of the addition a clear solution was formed and the reaction started to reflux. The reaction mixture was kept under reflux for 2 h. After cooling to room temperature the mixture was evaporated to dryness at 40C. The crude product was triturated in diethyl ether, and the insoluble compound was filtered off, washed with diethyl ether, and finally dried in vacuo at room temperature over P2O5 overnight. The product was obtained in form of colorless needles.
With copper(l) iodide; potassium carbonate; In ISOPROPYLAMIDE; at 115℃; for 6h;
B-C Moiety 10: [Show Image] <strong>[114872-98-9](R)-2-Amino-3-(2,4-dichloro-phenyl)-propionic acid</strong> (700 mg), K2CO3 (621 mg), and Cul (57 mg) were dissolved in DMA (10 ml). 4-Bromo-2-methylpyridine (312 mul) was added and the mixture was stirred at 115C for 6 h. The solvent was evaporated in vacuo and to the obtained residue were added MeCN (40 ml) and water (6 ml). The mixture was filtrated and the solution was evaporated in vacuo. The crude product was purified by preparative HPLC-MS.
Intermediate A2): [Show Image] To a mixture of <strong>[114872-98-9]D-2,4-dichlorophenylalanine</strong> (700 mg), 1,3-dibromobutane (424 mul) and 1 M aqueous NaOH (3 ml) in ethanol (7 ml) was added dropwise 1 M aqueous NaOH (7.5 ml) under reflux condition. The reaction mixture was kept under reflux for 18 h. The reaction mixture was cooled down and acidified to pH 1-2 with 5 N HCl. The solvents were evaporated and the yellow residue was dried over Sicapent under vacuum overnight. The residue was extracted with hot ethanol (40 ml) and filtered. The filtrate was evaporated to dryness and the solid was dissolved in hot ethanol (15 ml) and ether (200 ml) was added. A beige solid was starting to precipitate. The suspension was put in the fridge overnight and filtered. The filtrate was evaporated to dryness. The crude product was dissolved in a mixture of methanol (6.3 ml) and toluene (25 ml) and trimethylsilyldiazomethane (2 M in hexane, 2.53 ml) was added dropwise at 0C. The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated and the crude product was subjected to column chromatography.
With copper(l) iodide; potassium carbonate; In ISOPROPYLAMIDE; at 110℃; for 4h;
B-C Moiety 11: B-C Moiety 11: [Show Image] <strong>[114872-98-9](R)-2-Amino-3-(2,4-dichloro-phenyl)-propionic acid</strong> (500 mg), K2CO3 (700 mg), and Cul (50 mg) were dissolved in DMA (5 ml). 3-Bromopyridine (440 mul) was added and the mixture was stirred at 110C for 4 h. The solvent was evaporated in vacuo and to the obtained residue were added MeCN (30 ml) and water (8 ml). The mixture was filtrated and the solution was evaporated in vacuo. The crude product was purified by preparative HPLC-MS.
Synthesis of B-C Moieties: B-C Moiety 1: Intermediate A1): [Show Image] To a mixture of <strong>[114872-98-9]D-2,4-dichlorophenylalanine</strong> (700 mg), 1,3-dibromopropane (364 mul) and 1 M aqueous NaOH (3 ml) in ethanol (7 ml) was added dropwise 1 M aqueous NaOH (7.5 ml) under reflux condition. The reaction mixture was kept under reflux for 18 h. 1,3-Dibromopropane (152 mul) was added and the reaction mixture was kept under reflux for another 6 h. The reaction mixture was cooled down and acidified to pH 1-2 with 5 N HCl. The solvents were evaporated and the yellow residue was dried over Sicapent under vacuum overnight. The residue was extracted with hot ethanol (40 ml) and filtered. The filtrate was evaporated to dryness and the solid was dissolved in hot ethanol (50 ml), and ether (100 ml) was added. A white solid was starting to precipitate. The suspension was put in the fridge overnight and filtered. The filtrate was evaporated to dryness. The crude product was dissolved in a mixture of methanol (9 ml) and toluene (35 ml) and trimethylsilyldiazomethane (2 M in hexane, 2.54 ml) was added dropwise at 0C. The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated and the crude product was subjected to column chromatography.
B-C Moiety 4: [Show Image] A mixture of <strong>[114872-98-9]D-2,4-dichlorophenylalanine</strong> (100 mg) and bis-(2-bromoethyl) ether (64 mul) were dissolved in 1 M NaOH (0.4 ml) and ethanol (1 ml). The mixture was heated to reflux. 1 M NaOH (1.1 ml) was added dropwise over a period of 6 h. The reaction was kept under reflux for another 12 h. Bis-(2-bromoethyl) ether (27 mul) and 1 M NaOH (300 mul) were added and the reaction was kept under reflux for 10 h. The reaction mixture was cooled down to room temperature and acidified to pH 1-2 with 6 M HCl (250 mul). The solvents were evaporated and the yellow residue was dried over Sicapent under vacuum. The crude product was extracted with hot ethanol, concentrated to half of the volume and diethyl ether was added to the solution. The solution was filtered, the filtrate concentrated and warm ethanol (1 ml) was added to dissolve it back followed by diethyl ether (13 ml). A semi solid formed on the wall of the flask. Ethanol (200 mul) was added and a white solid started to crush out. The flask was kept in the fridge for 16 h. The white precipitate was filtered off and rinsed with diethyl ether to yield a white powder.