A New Highly Selective 5-ht <sub> 1 </ Sub> Receptor Agonist Sumatriptan Study Of The Synthesis Of New Routes, The Two Pyrrole Synthesis Method Study

Highly selective 5-HT1 receptor agonist Sumatriptan is the best choice in the treatment of migraine nowadays. The synthetic route of this drug have applied for the patent in China. In order to circumvent the monopoly of the foreign patent and introduce this new drug into our country, new routes for synthesis of Sumatriptan were studied and explored.There are two key points in the patent route: 1) Fischer indole synthesis; 2) methylation of ethyl amino group in 3-position of indole by means of condensation of amino group with formic aldehyde, then reduction with NaBH4. The new route must avoid these two points, so two strategies including eight synthetic routes were designed and studied.The first strategy: ethyl 4-[4-(N-methylsulfamylmethyl)-N-protected-anilino]-acetoacetate as intermediate by cyclization, acylamide exchange and reduction to synthesize Sumatriptan. The result is: the intermediate was synthesized smoothly, but failed to cyclize, though many methods were attempted. The structure of the byproducts in cyclolization were identified.The second strategy: 5-(N-methylsulfamylmethyl)-lH-indole was synthesized by Friedel-Crafts reaction through 2-[4-(N-methylsulfamylmethyl)-N-methylsulfonyl-anilinojacetaldehyde diethyl acetal, then the side chain 2-(N, N-dimethyl-amino)ethyl was introduced onto the 3-position of the substituted indole by Grignard reaction. This route was thoroughly different from that of the foreign patent, the synthesis of 2-[4-(N-methylsulfamylmethyl)-N-methylsulfonyl-anilino]acetaldehyde diethyl acetal was mature and the yield was stable. But the yields of cyclization and Grignard reaction were rather low. The reaction conditions still need to be improved.In the process of synthesis of 5-(N-methylsulfamylmethyl)-lH-indole by Reissert method, l-(N-methylsulfamyl)-2-hydroxyl-l-(3-methyl-4-nitro)phenyl-propenoic acid was separated. After derivatization, by using NMR technology and computer imitation of lowest-energy conformation method, the structure of this compound and the configuration of the derivative were confirmed.In this part of the thesis, more than forty compounds were synthesized, among them thirty were obtained for the first time. The reaction between ethyl 3-bromopyruvate and p-substituted anilines was found to involve the unexpected participation of acetone (solvent) forming N-aryl-2- methyl-4-carboxylate pyrroles. It seemed to be a new method of pyrrole synthesis with no literature precedent. Using the NMR techniques, the structure pattern of products of this new reaction was studied and the unique character of p- methoxyaniline in the reaction was also discussed. This one-pot pyrrole synthesis seemed to be a new variant of Knorr's method from the mechanism viewpoint.Several factors influencing this new reaction such as the structure, steric effect, electronegativity of the substituents and the solvent, acid-scavenging reagent were studied systematically:1. Amines:ⅰ) The influences of p-substituents and steric effects of anilines were studied. The yield and the structure of the products were influenced by the electronegativities of p-substituents,ⅱ) Under the same conditions, the reaction of aliphatic amines was unsuccessful.2. Ketones: The feasibility with aliphatic ketones and aromatic ketones in this reaction were studied,ⅰ) With aliphatic acyclic and cyclic ketones, the reaction went on smoothly and N-aryl-indole-3-carboxylate was synthesized successfully with this method by dehydrogenation of the product of reaction with cyclohexanone,ⅱ) The products of aliphatic-aromatic ketones didnot follow the general route of this reaction.3.α-Bromocarbonyl compounds: Unlike ethyl 3-bromopyruvate, ethyl 4- bromoacetoacetate didnot lead to cyclization to produce the pyrrole-acetate but stop short at the open chain intermediate(N-substituted aniline) which was invulnerable to attacks by the ubiquitous acetone solvent.4. The possibility of using nonketonic solvent was studied. The success of using tetrahydrofuran as solvent in place of ketone made it possible to reduce the amount of ketone to equimolar amount.5. The necessity of acid-scavenging agent was studied. Apart from anilines as acid- scavenging agent, addition of other basic acid-scavenging agent was necessary; otherwise the yield of reaction product would be lowered.