Improved post-treatment method of valsartan reaction mixed liquid

Abstract

The invention provides an improved post-treatment method of valsartan reaction mixed liquid. The method comprises the steps that N-[(2-cyanobiphenyl-4-yl)methyl]-N-(1-oxoamyl)-L-valine methyl ester and azide make cyclization reaction in a non-amide solvent, an alkaline reaction mixture containing valsartan and obtained through ester hydration is added into sodium nitrite which is enough to quenchthe rest azide while not being too much overdose under an alkaline condition, hydrochloric acid is acidified to be weak acid in a proper temperature range, after an organic phase is extracted, filtered and separated, a water layer is removed or filtered after water washing is conducted, water and an organic solvent which is immiscible in water are added at proper temperature, acidifying is conducted till pH is no higher than 1.0, the water layer is separated, washing, water diversion and concentration are conducted, and ethyl acetate is crystalized to obtain a crude product. The post-treatmentmethod greatly reduces generation of valsartan potential genotoxic nitrous impurity V320, highly toxic N-nitrosodimethylamine NDMA, N-nitrosodiethylamine NDEA and azide is left, the safety of valsartan usage is ensured, and industrialization can be achieved easily.

Description

technical field [0001] The invention relates to the field of synthesis of medicines and medicine intermediates, in particular to an improved post-treatment method for a valsartan reaction mixture. Background technique [0002] Valsartan (Valsartan), chemical name: N -valeryl- N -[[2'-( 1H -Tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- L - Valine, whose structure is shown in formula (I), is an angiotensin II receptor antagonist (ARB) developed by Swiss Novartis. It has the advantages of long-lasting and stable blood pressure lowering effect, less side effects and can be used in combination with other sartan drugs. ". It has become the first-line drug for the treatment of hypertension and plays an important role in clinical practice. [0003] [0004] The pharmacophore in the valsartan drug molecule is biphenyltetrazolium. In industrial production, its construction usually uses a biphenylcyano compound and an azide compound to undergo a cycloaddition reaction under Lewi...

AI Technical Summary

Problems solved by technology

[0006] In order to improve the conversion rate of valsartan cyano intermediate (II) in production, usually need to use excessive azide, so in the aftertreatment process, must have to carry out harmless treatment step for excessive azide, otherwise, in Toxic azido acid will be produced in the subsequent process, and materials containing azide are prone to explosion accidents when they encounter heavy metals such as copper during the transfer process

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