A kind of preparation method of clopidogrel free base

Abstract

The invention relates to a low-cost simple method for preparing clopidogrel free alkali. The method comprises the following steps: taking (S)-2-chlorophenyl glycine methyl ester as an initial raw material, and sequentially carrying out an N,N-bisubstitution reaction, a solid sodium methoxide intramolecular condensation reaction, a 1,2-dihalogenation ethyl acetate substitution reaction, a hydrogen sulfate mercaptolation reaction and sulfuric acid decarboxylation cyclization with methyl acrylate in a pot, thereby obtaining the clopidogrel free alkali. The clopidogrel free alkali is prepared by adopting a one-pot process, expensive raw materials such as thiopheneethanol or other thiophene derivatives are not used, the raw materials are low in price and readily available, the reaction process is simple and convenient, the process is safe and environment-friendly, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of clopidogrel free base, which belongs to the field of pharmaceutical biochemical industry. Background technique [0002] Clopidogrel free base (Ⅰ), the chemical name is (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4 -hydrogen)-methyl acetate is an anti-platelet coagulant drug successfully developed by SANOFI Company of France in 1986. Its bisulfate is clinically used and widely used in the treatment and prevention of myocardial infarction, atherosclerosis, acute coronary Cardiovascular diseases such as arterial syndrome, as well as the prevention of postoperative coronary stenosis and thrombotic complications. Compared with similar antiplatelet drugs, clopidogrel bisulfate (clopidogrel for short) has the advantages of good curative effect, less adverse reactions, and low treatment cost. It has become a blockbuster drug since it was launched on the market. been widely concerned. There a...

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Problems solved by technology

[0007] The price of 4,5,6,7-tetrahydrothiophene[3,2-c]pyridine used in reaction scheme 1 is high, and a large amount of (R)-clopidogrel remains after the resolution of (-)-camphorsulfonic acid, so that (S )-clopidogrel high cost

The raw materials used in reaction scheme 2 are relatively cheap, and the resolution operation is carried out in the initial step, which has obvious advantages compared with reaction scheme 1. Reaction scheme 2 is generally used at present, but this route 2 still uses the higher 2-(2-thienyl ) ethanol p-benzenesulfonate, and the preparation of 2-(2-thienyl) ethanol p-benzenesulfonate is relatively cumbersome. Generally, 2-bromothiophene is prepared by thiophene bromination, 2-bromothiophene Grignard, and ring Oxyethane reacts to prepare 2-thiophene ethanol, and then reacts with p-toluenesulfonyl chloride sulfonylation to obtain

The reaction route is long and the cost is relatively high; on the other hand, the reaction produces a large amount of waste water, which is poor in environmental protection and difficult to meet the requirements of green production

[0008] Although the patent protection period of clopidogrel free base and type I has expired, the high production cost of clopidogrel still cannot be widely used

Due to the high price of clopidogrel, most patients undergoing arterial bypass surgery or arterial stents cannot afford long-term medication after surgery, and cannot effectively avoid blood clotting to cause new infarction, and the incidence of sudden cardiac death is still high

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