Process of preparing a thrombin specific inhibitor

摘要

A process of preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 and R2 represent H; or either R1 represents ethyl and R2 represents n-hexyloxycarbonyl that applies to industrial scale, novel intermediates useful for the preparation thereof, and processes of preparing said intermediates.;

主权项

1. A process of preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 and R2 represent H; or either R1 represents ethyl and R2 represents n-hexyloxycarbonyl, comprising: a) providing the compound of formula (III-HCl) as a solid; b) reacting the compound of formula (III-HCl) with an amount comprised between 3-5 mol of ammonia or of an ammonium salt for each mol of the compound of formula (III-HCl) to obtain the compound of formula (II-HCl); and isolating the product obtained as a solid; c) converting the compound of formula (II-HCl) obtained into a compound of formula (I); wherein the conversion comprises reacting the compound of formula (II-HCl) with a base in a solvent, to give a compound of formula (I) wherein R1 and R2 represent H; or alternatively, the conversion comprises reacting the compound of formula (II-HCl) with a compound of formula (XI) wherein X is a halogen, optionally in the presence of a base, to give a compound of formula (I) wherein R1 represents ethyl and R2 represents n-hexyloxycarbonyl; and d) optionally converting the compound of formula (I) into a pharmaceutically acceptable salt thereof by treatment with an acid, or either converting a pharmaceutically acceptable salt of the compound of formula (I) into a compound of formula (I) by treatment with a base, or either converting a salt of the compound of formula (I) into another salt of the compound of formula (I) by ion exchange.