PROCESS FOR PREPARING ADRENALINE

摘要

1. Process for preparing adrenaline or an addition salt of adrenaline, characterised in that in a first step N-protected adrenalone as the educt is subjected to asymmetric hydrogenation with [Rh(COD)Cl]2 and a chiral, bidentate phosphine ligand as catalyst system, then in a second step the N-protected adrenaline produced is precipitated in the basic range and in a third step the N protecting group is cleaved in the acid range. 2. Process according to claim 1, characterised in that in the first step N-benzyl-adrenalone 1 is used as educt, which is reacted in the first reaction step to form N-benzyladrenaline 2, which is precipitated in the second step and is reacted in the third step by cleaving the benzyl nitrogen protecting group by hydrogenation in the presence of a palladium catalyst, preferably palladium on charcoal, to obtain adrenaline or an acid addition salt thereof. 3. Process according to claim 1 or 2, characterised in that the phosphine ligand is (2R, 4R)-4-(dicyclohexylphosphino)-2-(diphenylphosphino-methyl)-N-methyl-aminocarbonyl-pyrrolidine. 4. Process according to claim 1 or 2, characterised in that the phosphine ligand is polymer-bound (2R, 4R)-4-(dicyclohexylphosphino)-2-(diphenylphosphino methyl)-N-methyl-aminocarbonyl-pyrrolidine. 5. Process according to any one of claims 1 to 4, characterised in that the asymmetric hydrogenation is carried out in a temperature range from 40 degree C to 70 degree C, preferably 45 degree C to 55 degree C. 6. Process according to one of the preceding claims 1 to 5, characterised in that the asymmetric hydrogenation is carried out under a pressure of 10x10<5> Pa to 100x10<5> Pa, preferably 10 to 50x10<5> Pa. 7. Process according to claim 6, characterised in that the asymmetric hydrogenation is carried out under a pressure of 15 to 25x10<5> Pa. 8. Process according to one of claims 1 to 7, characterised in that the asymmetric hydrogenation is carried out in a protic solvent. 9. Process according to claim 8, characterised in that the asymmetric hydrogenation is carried out in methanol, ethanol, propanol or isopropanol as solvent. 10. Process according to claim 9, characterised in that the asymmetric hydrogenation is carried out in methanol as solvent. 11. Process according to one of the preceding claims 9 or 10, characterised in that the solvent for the asymmetric hydrogenation contains water. 12. Process according to one of the preceding claims 1 to 11, characterised in that the molar ratio of educt to the rhodium catalyst in the asymmetric hydrogenation is between 500:1 and 10000:1, preferably between 500:1 and 3000:1. 13. Process according to claim 12, characterised in that the molar ratio of educt to the rhodium catalyst in the asymmetric hydrogenation is between 1000:1 and 2000:1. 14. Process according to one of the preceding claims 1 to 13, characterised in that the rhodium catalyst for the asymmetric hydrogenation is used as a pre-prepared solution. 15. Process according to one of the preceding claims 1 to 13, characterised in that the rhodium catalyst for the asymmetric hydrogenation is produced in situ. 16. Process according to one of the preceding claims 1 to 14, characterised in that the reaction time for the asymmetric hydrogenation is between 2 and 8 hours, preferably between 4 and 6 hours. 17. Process according to one of the preceding claims 1 to 16, characterised in that in the second reaction step a nitrogen base, preferably ammonia, is used as the base for precipitating the N-protected adrenaline. 18. Process according to one of the preceding claims 1 to 17, characterised in that in the third reaction step sulphuric acid, hydrochloric acid or phosphoric acid, preferably sulphuric acid, is used to acidify the solvent. 19. Process according to one of the preceding claims 1 to 18, characterised in that the pH of the third step is between 5 and 6. 20. Process according to one of the preceding claims 1 to 19, characterised in that the reaction temperature of the third reaction step is 40 to 80 degree C, preferably 50 to 70 degree C and most preferably 60 degree C.