Drug Intermediates 3 - Thiophene Malonic Acid Synthesis

As an important side chain intermediate, 3-thiophenemalonic acid (3-TMA) can react with 6APA to produce Ticarcillin which can be prepared from Benzylpenicillin and penicillin analysis by degradation under alkaline conditions. The chemical reaction is shown as below:Timentin, the second effective antibiotics (produced by Smith Kline Beecham company ) can be composed by dispensation of Ticarcillin with Potassium Clavulanate in 15:1 proportion. Timentin firstly came into the market in 1986 in America.It has effective activities against Aeruginosav (90%) and it is stable for β-lactamase generated by chemical sproof Aeruginosav. But it is easier to be desyroyed by β-lactamase generated by Escherichia coli , bacillus proteus mirabilis and several Aeruginosav. It has synergistic action against Aeruginosav when acted with gentamycin and polymgxin . It's antibacterial activities against Aeruginosav is 2-4 times stronger than Carbenicillin. Timentin can also treat Septicemia, Pyelonephritis, Cystitis, Respiratory, Urinary Tract infection, Leucocythemia and the secondary infection of patients with malignant tumor, besides of these it can treat Typhoid effectively. The annual sales of Timentin was about 200 million dollars. Presently in clinic application, timentin is depended on importation in our country. There is no Timentin produced in our country in the market.In the subject we studied the routes of 3-thiophenemalonic acid synthesis. It includes three aspects : In the first step, we analyzed the five membered heterocyclic structures of thiophene. Because the beta position of thiophene is less active than the alpha position, that is to say that the alpha position of thiophene is more active, we ingeniously designed the routes of the reaction. First, we must produce 2.3.5-tribromines thiophene , then remove bromine of alpha position and we can gain 3- bromine thiophene and avoid the formation of by-product in the alpha position. In the second step, contrasting the chemical reaction of four kinds of metallorganic compound, we designed two solutions of synthesizing 3-Thienylpropanedioic acid and put the two solutions into practice based of these , we set up two methods of and using it in experiments . Finally through the second solution and using the characteristic that copper lithiumreagent doesn't attack the hydroxyl, we grafted diethyl bromomalonate on the heterocycle of thiophene and established the synthetic routes of 3- thiophene malonic acid(T M A). In the last step, we explored the best conditions of reaction so as to obtain the product of good crystal and high productivity (76%). Compared with the article which was reported at present (only one related article from the retrieval in our country exists), this synthetic routes and technological design is reasonable, with fewer steps, simple skills of purifying and the conditions of reaction is easy to control. The overall result is satisfying. Moreover, from the retrieval we know that the reaction of grafts has not been reported in the 3rd position of thiophene but derivatives of 2- thiophene are more. We believe that the design method will lead to a series of product of 3-thiophene derivatives.