| With improving people’s living standards, people’s habits and diets occura great change. The high viscosity of the blood, the high lipoprotein of theblood and the high cholesterol statecan of the blood caused by more andmore intake of high fat foods, as well as smoking, drinking and other badhabits easily lead to the formation of blood clots. Each year in our countrythere are about300millions stroke incidence,150million of them are newand it has an upward trend in recent years. The existing stroke patients(recovery) are about500million peoples.75%of them is loss of labor andover40%will be disability and about10%of patients will relapse. In China,ischemic stroke is the main types of stroke, because it accounted for70%to80%of the incidence of the entire stroke. There are many drugs for thetreatment of acute ischemic stroke in the domestic market, but most of themare chemical and biological agents obtained by biological extraction andeasily cause allergic reaction of the body’s own risk.The advent of argatrobanfor the majority of patients with cerebrovascular brought the gospel.Argatroban is a small molecule of a synthetic monovalent direct thrombininhibitors, and it can be selectively and reversibly with the thrombin catalyticsite binding, direct inactivation of thrombin. In addition, it does not depend onthe level of antithrombin in vivo. Argatroban could not only inhibit the freethrombin, but also can inhibit clot-bound thrombin. Because of its smallmolecular weight, it is also able to enter the thrombus internal thrombosis toinactivate internal thrombin. In short, the argatroban can inhibit systemichypercoagulability and play a role of local thrombosis anticoagulant auxiliaryof thrombolysis.Argatroban was developed as the first synthetic antithrombotic drugs byJapan’s Mitsubishi, Institute of Chemistry. It firstly used in the clinicaltreatment of peripheral arterial occlusive disease, and then began to be usedfor the treatment of acute cerebral thrombosis. The U.S. Food and Drug Administration (FDA) in2000approved SmithKline Beecham and TexasBitechnology Company that argatroban as an injectable antithrombotic drugcan be used in the treatment and prevention of thrombosis andheparin-induced autoimmune diseases-platelet thrombocytopenia (HIT), aswell as for the need percutaneous coronary intervention the intraoperative(PCI) treatment of patients. In2005, a new drug for the treatment of acutecerebral thrombosis named "Dabbeh-argatroban " was approved by the StateFood and Drug Administration, and was included in the11th Five-Year planissued by the National863project and the Ministry of Science andTechnology National issued the new product certificate. This drug isacclaimed in clinical, but there is mainly a vendor to provide the raw meterialsof argatroban. Due to this drug is too expensive, the synthesis process stillneeds to be improved, so the development of this drug have a great prospect.Argatroban:(2R,4R)-4-methyl-1-[N2-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-2-piperidinecarboxylic acid.Objective: The aim is to accomplish the synthesis and the analysismethods of Argatroban.Methods: Using aniline (2) as the raw material that reacts with thepropionic acid to obtain propionanilide (3), then with phosphorus oxychlorideand N, N-dimethyl formamide, occurring cyclization to give2-chloro-3-methyl-quinoline (4). And then3-methylquinoline (5) is preparedby hydrogen and dechlorination of the compound(4) under the condition ofPd/C and H2. The compound(4) reacts with chlorosulfonic acid in thecondition of sodium sulfate and thionyl chloride to get compound(6) called3-methylquinoline-8-sulfonyl chloride (6), which condenses withNG-nitro-L-arginine (8)prepared by the compound(7) to give intermediateN2-(3-methyl-8-quinoline-sulfonyl)-NG-nitro-L-arginine(9),4-methyl-N-chloropiperidine (11)can be obtained from4-methylpiperidine (10) with sodiumhypochlorite solution. In the conditions of potassium hydroxide, elimination isoccured to give4-methyl-3,4,5,6-tetrahydropyridine (12). And then reactingwith sodium bisulfite to give4-methylpiperidin-2-sulfonate (13) that substituted by sodium cyanide to obtain2-cyano-4-methylpiperidine (14), thecompound(14) is hydrolyzed by6N hydrochloric acid into4-methyl-2-piperidinecarboxy (15). And then the compound(15) reacts withthionyl chloride and ethanol to give ethyl4-methyl-2-piperidinecarboxylate(16), followed by fractionation under reduced pressure to givetrans-4-methyl-2-piperidinecarboxylate(17), and then split by L-tartaric acidsto give ethyl (2R,4R)-4-methy-2-piperidinecarboxylic (18), the compound(18)with intermediate9under conditions of phosphorus oxychloride andtriethylamine gives ethyl (2R,4R)-1-[NG-nitro-N2-(3-methyl-8-quinoline-sulfonyl)-L-arginine]-4-methyl-2-piperidine carboxyliate (19), followedhydrolysis by sodium hydroxid to obtain (2R,4R)-1-[NG-nitro-N2-(3-methyl-8-quinolinesulfonyl)-L-arginine]-4-methyl-2-piperidinecarbox-ylic acid (20),then target compounds (1) can be obtained by hydrogenation reduction.Through melting point, Mass spectrometry, NMR and other means,intermediate and the target compound were identified, and the purity ofobjects was determined by high performance liquid chromatography.Results: Successfully synthesize the target compound(Argatroban) as awhite powder with the total yield of2.18%and analyze it. mp.178.7~182.5℃.The content of Argatroban is99.2%that is measured by area normalizationmethod.Conclusion: In this research, aniline as raw material, via8stepsreactions synthesize the target compound1(Argatroban), the Synthetic routehas mild reaction conditions, high yield, low cost, and the product is easy toseparation and purification. |
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