Preparation and purification method of valsartan

Abstract

The invention relates to the field of medicinal chemistry and discloses a preparation and purification method of valsartan. The method comprises the steps of (S1) adding L-valine and alcohol to a reaction kettle, slowly dropwise adding thionyl chloride, carrying out heating reflux reaction, adding isopropyl acetate for pulping, carrying out suction filtration to obtain an intermediate 1; (S2) carrying out nucleophilic reaction on the intermediate 1 and a starting material 2 in a solvent under an alkaline condition to obtain an intermediate 2; (S3) carrying out nucleophilic reaction on the intermediate 2 and valeryl chloride in the solvent under the alkaline condition to obtain an intermediate 3; and (S4) carrying out cyclization reaction on the intermediate 3, sodium azide and a catalyst ((-)-sparteine-Cu (II) complex) in the solvent, washing, crystallizing and drying to obtain the valsartan. The sodium azide and the catalyst ((-)-sparteine-Cu (II) complex) are used in the cyclization reaction, and the cyclization yield can reach 90%. According to the purification method, the purity of the raw materials of the valsartan is greater than 99.99%, the content of a solvent residue (ethyl acetate) is smaller than 0.5%, the content of a specific impurity is smaller than 0.1%, other unknown individual impurities are avoided and an enantiomer impurity is not detected.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, more specifically, to a method for preparing and purifying valsartan. Background technique [0002] Valsartan (valsartan), chemical name N-(1-oxopentyl) N-[4-[2-(1H-tetrazol-5 base) phenyl] benzyl]-L-valine, is the following Another new type of antihypertensive drug after calcium ion channel blockers and angiotensin converting enzyme inhibitors (ACEI), it is an angiotensin II (angiotensin II) AT receptor antagonist, avoiding calcium antagonists and ACEI It has the advantages of significant curative effect and good tolerance. [0003] There are many synthetic patent reports of existing valsartan, and the methods are different. The main synthetic methods are as follows: [0004] Among them, US5399578 is the first to report the use of 2'-cyano-4-formyl biphenyl as a raw material, and the p-toluenesulfonate of protected L-valine benzyl ester through reductive amination reaction, n-valerylation R...

AI Technical Summary

Problems solved by technology

This route performs ester hydrolysis under acidic conditions, the conversion rate is not high, and pyridine is used, which seriously pollutes the environment

[0008] CN1709877A uses catalysts such as triethylamine, ammonium chloride, and TEBA to synthesize tetrazole in benzene or toluene. In this invention, a toxic organic solvent is used, and the related substances and isomers of the final product are not involved

[0009] CN1775764A has introduced a kind of method that trifluoroformic acid nitrile is used as catalyst to catalyze the synthesis of tetrazolium compounds at 20~150 ℃, but it is used for synthesizing valsartan, can lead to the valsartan configuration inversion at high temperature, isomers are different qualified

[0010] CN101016269A mentions a purification process of a novel tetrazole derivative. Although the purity is high, multiple extractions and pH adjustment are required in the purification, and the process is relatively cumbersome

[0011] CN101270096A uses triethylamine hydrochloride as a catalyst to synthesize the tetrazolium mother nucleus. The process is simple and the reaction time is long. Although the reaction time can be shortened by using chlorotoluene, the amount of subsequent steaming to remove ethyl acetate is difficult to control, and the product yield and quality can not be well controlled

[0012] CN101200455A uses trialkyltin chloride or triethylamine hydrochloride to cyclize to obtain the tetrazolium mother nucleus, but the cyclization temperature is 100-150°C, and the reaction time is 15-30h, which is not suitable for large-scale production

[0013] CN101450917A mentioned for the first time the use of catalysts such as zinc chloride to synthesize the tetrazolium core, but the use of more polar n-butanol in the reaction made the overall yield lower

[0014] CN101362728A uses tributyltin chloride to synthesize the tetrazolium mother nucleus, tributyltin chloride is difficult to completely remove in subsequent treatment, and the content of tin in the finished product is difficult to control at 1ppm

[0016] CN102863398A Synthesizes tetrazole by using rare earth metal organochloride bis(methylcyclopentadiene) samarium chloride, this type of catalyst is rare and difficult to obtain

[0017] CN105801507A introduces a preparation method for synthesizing 1-(3-bromophenyl)-1H-tetrazole using copper salt (cuprous iodide, cuprous chloride, etc.), but this invention does not involve tetrazole Synthesis of mother nuclei

[0018] CN105906611A introduces a method for synthesizing tetrazole by using azidotrimethylsilane, the catalyst is particularly active and difficult to operate

Images