Study On The Synthesis Process Of Galanthamine

The natural Amaryllidacae alkaloid galanthamine, an acetylcholine enzyme inhibitor, has been used clinically for treatment of myasthenia gravis and other neurological illnesses such as poliomyelitis, as an anti-curare agent, and as a parasympathomimetic. More importantly, it has been approved for the treatment of Alzheimer's disease. Galanthamine is produced by isolation from botanical sources. This process was very trouble. Despite renewed efforts, these sources are not suitable for generation of large enough quantities of galanthamine. Considering the problem of total synthesis of galanthamine, a new technology of total synthesis of the galanthamine was put forward.There are dissertation mainly includes three parts: total synthesis of Galanthamine, semi-synthesis of Galanthamine and transformation of its analogues.With 1,2-dimethoxybenzene and tyrosine as the initial material, racemic galanthamine was prepared by five steps including bromination, condensation and reduction, formylation, oxidation coupling and reduction.3,4-Dimethoxybenzaldehyde was prepared from 1,2-dimethoxybenzene in 70.0% total yield via chlorination, salt formation, hydrolysis reaction. This product with Br2 was obtained 2-bromo-4,5-hydroxymethoxybenzaldehyde through bromination.The Intermediates were in turn hydrolysed the 6-position methoxy to hydoxy group, in the presence of molar quantity methionine, by concentrated sulfuric acid, with to give 2-bromo-5-hydroxy-4-methoxy-benzaldehyde. Compound yields is 85.0%. The neighbou effect and Structural stability in the bromination steps were suggested and discussed. The mechanism of methionine in the hydrolysis may involved with formation of the multiple hydrogen bonded association complex.Tyromine was prepared from tyramine via decarboxylation reaction in 71.2% yield. Then the condensation reaction of 2-bromo-5-hydroxy-4-methoxybenzaldehyde with tyramine producted in 96.5% yield. The yield of reduction was 95.0% with reducing agent. The effects of temperature, catalyst and solvent on cell reaction were studied. The yield of formylation with intermediate of reduction reaction and formic acid is 87.7% in the presence of microwave irradiation.4a,5,9,10,11,12-Hexahydro-1-bromo-11 -formyl -3-methoxy -6H-benzofuro[3a,3,2-ef][2] benzazepine-6-one, was prepared from product of formylation by chemical and indirectly electrochemical oxidation with [Fe(CN)₆]^4-/ [Fe(CN)₆]^3- as the electron carrier and PEG 200 as the PTC. The overall yield of the titled compound was increased from 54%( by chemical oxidation) to 62.4% with the optimized reaction condition of K₄[Fe(CN)]₆ concentration: 0.040mol L-1, temperature: 40℃, current density: 3.5A dm-2, electrolytic time: 1.5hr.The yield of reduction was 83.0% with LiAlH₄ as the reducing agent. A chiral resolving reagent (+)-2,3-di-(p-toluoyl)-tartaric acid was prepared from D-tartaric acid and p-toluic acid using p-toluene sulfonic acid as a catalyst and toluene as a solvent. (±)-galanthamine was resolved by Galanthamine (+)-2,3-di(p-toluoyl)-tartate, and such, on a D001 macroporous strong acidic cation exchange resin. The yield and optical purity of Galanthamine were 66.1% and 97%. The recovery of (+)-2,3-di-(p-toluyl)-tartaric acid was 83.0%. The Galanthamine was totally synthesized from 1,2-dimethoxybenzene and tyrosine.Yield and optical purity of the Galanthamine are 20.0% and 30% in optical resolution by method of inducing crystal.Lycoramine was dehydrogenated selectively in the presence of 9 % rare earths metal hydride at 240°C, semi-synthesis of galanthamine was obtained in 45.9 % yield. The effects of reaction conditions such as reaction temperature, reaction time, and the quantity of catalyst were discussed. The Values of activation energy were given to be 77.25 kJ/mol in Arrhenius equation. Single point energy was worked out at the AMI level to give eight results.With galanthamine as the initial material, was synthesized narwedine with MnC>2 as oxidant, epigalanthamine with NaBfLi as reducing agent, lycoramine with Pd/C as reducing agent, norgalanthamine with PCC, NaBtLt and FeSO4, respectivly. The yields were 80.2%, 39.5%, 95.4% and 27.3%, respectively.The chemical structures of the titled compounds and the key intermediates were confirmed by 'H-NMR, 13C-NMR, IK, MS, include GC/MS and LC/MS.