Improved tadalafil preparation method

Abstract

The invention belongs to the field of preparation of chemical raw medicaments, and more in particular relates to an improved preparation method for a phosphodiesterase 5 inhibitor tadalafil. A specific synthesis route is shown in the specification. The method comprises the following steps of performing Pictet-Spengler cyclization reaction and chloroacetyl chloride acylation on starting reactants (D-tryptophan methyl ester hydrochloride and piperonal) to obtain an intermediate product, directly performing subsequent reaction on the intermediate product without purification, preparing an intermediate 1-(1,3-benzodioxol-5-yl)-2-(chloracetyl)-2,3,4,9-tetrahydro-1H-pyridino-[3,4,-B]indol-3-thiophenate methyl by using a one-pot reaction method, performing column chromatography purification to obtain a single cis-isomer, and finally reacting the single cis-isomer with methylamine hydrochloride in the presence of an inorganic base to obtain the tadalafil.

Description

technical field

[0001] The invention belongs to the field of preparation of chemical raw materials, and more specifically relates to a preparation method of tadalafil, a phosphodiesterase 5 inhibitor. Background technique

[0002] Tadalafil (Tadalafil) is a phosphodiesterase type 5 (PDE5) inhibitor originally developed by GlaxoSmithKline (GSK), and then transferred to ICOS, and later by ICOS and Eli Lilly (EliLillv) Jointly developed and approved by the FDA in 2003, it was marketed in the United States as a drug for the treatment of male erectile dysfunction (MED).

[0003] The synthesis of tadalafil reported at present is mostly carried out with D-tryptophan methyl ester and piperonal as raw materials, and the difference is mainly in the intermediate cis-(1R,3R)-1-(1, 3-benzodioxolan-5-yl)-2-(chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-B]indole-3-carboxy In the preparation method of methyl ester (formula D), because the preparation method of the intermediate is differe...

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