General procedure for the synthesis of (S)-2-amino-3-(4-hydroxy-3-iodophenyl)propionic acid from L-tyrosine: L-tyrosine (147.3 kg, 813 mol, 1 eq.) and concentrated hydrochloric acid were added to a 3000 L reactor. Ammonia (25%, 1980kg, 13.5w) was then added to form a white suspension. The suspension was cooled to -10 to 0°C. At this temperature, iodine (223 kg, 878 mol, 1.08 eq.) was added in 40 batches, taking about 5 hours. After addition, stirring was continued at -10 to 0 °C for about 2 hours. Samples were diluted with water and analyzed by HPLC, which showed 86.4% of A7 (target product), 11.3% of diiodide and 2.3% of unreacted L-tyrosine. Subsequently, the reaction solution was concentrated under vacuum at 0 to 40 °C for 28 h until the pH of the residue was reduced to 9.6. The concentrated solution was cooled to 20-30 °C, at which temperature the pH was adjusted to 8 by dropwise addition of an aqueous 18% hydrochloric acid solution, taking about 10 h. The reaction solution was then concentrated in a vacuum at 0 to 40 °C for about 1 h. The reaction solution was then concentrated at 0 to 40 °C for about 1 h. The reaction solution was then concentrated in a vacuum at 0 to 40 °C for about 1 h. A7 (0.25 kg) was added as a crystal seed and stirring was continued at 20-30 °C for about 1 hour. Subsequently, the pH of the mixture was continuously adjusted to 7.4 with 18% aqueous hydrochloric acid solution over a period of 3 hours and stirred for 1 hour at each pH stage. Finally, stirring was continued for 2 hours at 20-30°C (in total, about 1200 kg of 18% aqueous hydrochloric acid solution was used for crystallization). The slurry was centrifuged and the wet filter cake was washed twice each with water (230 kg, 1.6 w, each time) and acetone (230 kg, 1.6 w, each time) sequentially. The solid was dried under vacuum at 50-60 °C for about 48 h to give A7 (156.6 kg) with a purity of 96% and a water content of 2.5% as a light brown solid in a yield of 62.6% (uncorrected; after deduction of 0.25 kg of A7 crystalline seed).
