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Since the 17th century, cinchona bark was used in Europe as an antifever drug, and then as a drug for treating malaria. Two alkaloids were isolated from the bark of the cinchona tree as far back as the 1820s (quinine and cinchonine) which are noncondensed biheterocycles containing two heterocyclic nucleus, quinoline and quinuclidine. Quinine is a methoxylated derivative of cinchonine. Quinine is the levorototary isomer of quinidine. Its structure consists of a quinoline ring, the fourth position of which is bounded by a hydroxy methylene bridge to a quinuclidine ring. The methoxy group at C6 of the quinoline ring and the vinyl group in the quinuclidine ring enhance the activity of the compound; however, they are not absolutely necessary for the compounds of this group to express antimalarial activity. Quinine has gained significant importance as a base structure for synthesizing numerous compounds with antimalarial activity. The synthesis of this drug is very complex and has been made in different ways, but it basically comes down to the ester condensation of 6-methoxyquinoline (quininic) acid esters (37.1.1.27) and N-benzoylhomomeroquinene (27.1.1.42), which can be made in various ways, and subsequent successive treatment of the resulting product with hypobromite and then with sodium ethoxide in order to create the quinuclidine fragment.

One of the methods of making the ethyl ester of quininic acid (37.1.1.27) that should be mentioned is the method described in the following scheme. Reacting p-anisidine and ace-toacetic ester in the presence of sulfuric acid gives 6-methoxylepidine (37.1.1.22). The hydroxyl group of this compound is replaced with a chlorine atom by reacting it with a mixture of phosphorus oxychloride and phosphorus pentachloride, giving 2-chloro-4-methyl-6-methoxyquinoline (37.1.1.23). Reducing this compound with hydrogen using a palladium catalyst removes the chlorine atom at C2 and gives 4-methyl-6-methoxyquinoline (37.1.1.24). Condensing this with benzaldehyde gives 2-(6-methoxy quinolinyl-4)-styrene (37.1.1.25), the double bond in which is oxidized using potassium permanganate to make 6-methoxyquinolinic acid—cinchonine (37.1.1.26), which is then converted into an ester (37.1.1.27) in the usual manner.

ch3 ch=ch-c6h5 COOH COOCjHs

C6H5CHO KMnO4 C2H5OH/H +

ch3 ch=ch-c6h5 COOH COOCjHs

C6H5CHO KMnO4 C2H5OH/H +

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