Preparation method of silodosin key intermediate

Abstract

The invention discloses a preparation method of a silodosin key intermediate, and belongs to the technical field of medicine synthesis. Carrying out Friedel-Crafts reaction on indoline and trichloroacetonitrile to obtain a compound 1; brominating to obtain a compound 2; then carrying out substitution with 2-(3-bromopropoxy) tetrahydro-2H-pyran to obtain a compound 3; then carrying out nucleophilic addition with (S)-epoxypropane or (R)-epoxypropane at an ultralow temperature to obtain a compound 4; then carrying out Mitsunobu reaction with phthalimide to obtain a compound 5 (configuration inversion) or esterifying with paratoluensulfonyl chloride, and reacting with potassium phthalimide under the condition of inorganic alkali to obtain the compound 5; reducing through hydrazine hydrate to obtain a compound 6; then removing tetrahydropyran protection from p-toluenesulfonic acid to obtain a compound 7; performing amino Boc protection under an alkaline condition to obtain a compound 8; esterifying with benzoyl chloride to obtain a compound 9; removing Boc protection with hydrochloric acid to obtain a compound 10; and salifying with L-tartaric acid to obtain a compound 11. Compared with the prior art, the preparation method has the advantages that cyano groups synthesized by Vilsmeier reaction, hydroxylamine oximation and acetic anhydride dehydration at the 7 site and introduction of amino groups at the 5 site through nitro groups or reductive amination are avoided, and heavy metals such as Pd/Pt/Zn and the like do not need to be used; the continuous operation of the whole steps is increased, the production cost of the silodosin intermediate is greatly reduced, and industrial large-scale production is facilitated.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, in particular to a preparation method of a key intermediate of silodosin. Background technique [0002] Sirodosin is an α1A receptor antagonist developed by Kissei Pharmaceutical Company of Japan. It was launched in Japan in May 2006 under the trade name Urief. Silodosin is clinically used to treat symptoms associated with benign prostatic hyperplasia (BPH) or hypertrophy. Most of the preparations of silodosin are capsule preparations, which were approved by the U.S. Food and Drug Administration in 2008. [0003] The key intermediate of silodosin, 5-[2(R)-aminopropyl]-1-[3-(benzoyloxy)propyl]-7 cyano-indoline tartrate, the current synthesis method is mainly It has its own characteristics in the 7-position cyano group and the 5-position chiral aminopropyl group, but it is more or less unavoidable that the 7-position is synthesized by Vilsmeier reaction, hydroxylamine oximation and acetic ...

AI Technical Summary

Problems solved by technology

[0003] The key intermediate of silodosin, 5-[2(R)-aminopropyl]-1-[3-(benzoyloxy)propyl]-7 cyano-indoline tartrate, is currently the main synthetic method The 7-position cyano group and the 5-position chiral aminopropyl group have their own characteristics, but it is more or less unavoidable that the 7-position synthesizes a cyano group through Vilsmeier reaction, hydroxylamine oximation and acetic anhydride dehydration, and the 5-position undergoes amino acid substitution, stacking Nitrogen sodium substitution, nitro reduction or L-tartaric acid resolution to synthesize the key intermediate of silodosin

However, there are more or less large-scale production safety problems in this way (such as the synthesis of cyano group by Vilsmeier reaction, hydroximation and acetic anhydride dehydration at the 7th position, and hydrocyanic acid will be generated during the dehydration process), and some explosive Sodium azide or Pd and other heavy metals are used to catalyze, so that the product has more or less heavy metal residues, etc.

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