This thesis is focused on the development of new synthetic processes for the production of already known Active Pharmaceutical Ingredients (APIs). The research work was performed in the laboratories of Dipharma Francis srl, a company which operates in the generic drug market. The launch of the generic version of a drug in the market often leads to lowering of product prices for both the branded product and the generic ones. For this reason, the process adopted to produce an API has to be innovative, efficient, safe and, of course, cheaper than the existing ones, in order to be competitive in the market. During my Ph.D. I worked on the synthesis of some APIs, in particular here I report the feasibility and development studies of an alternative process to produce silodosin. Silodosin is an API used as a treatment for the symptoms of Benign Prostatic Hyperplasia (BPH). In order to establish the synthetic strategy and to outline our freedom to operate, an accurate survey of the whole patent literature about silodosin has been done. During the feasibility study several synthetic approaches have been tried in order to functionalise indoline at positions 5 and 7. A copper(I) catalysed C-arylation reaction and a regioselective electrophilic aromatic substitution revealed to be the best choices to introduce respectively substituents in position 5 and 7 of indoline. The synthesis continued with a diastereoselective reductive amination which after crystallisation yielded optically pure amine intermediate that is the key intermediate for the synthesis of silodosin and ended converting amine intermediate into Silodosin using already reported procedures. Our new process to prepare silodosin starting from commercially available and cheap indoline consists of 11 steps. The whole synthetic route has been performed in gram scale using only 4 purifications of key intermediates. Silodosin has been finally obtained in a 10% overall yield, with a purity greater than 99% measured by HPLC and an optical purity greater than 99% measured by HPLC on chiral stationary phase.

NEW SYNTHETIC PROCESSES FOR THE APIS INDUSTRIAL PRODUCTION: THE CASE OF SILODOSIN / F. Calogero ; tutor: D. Passarella ; co-tutor: E. Attolino (Dipharma Francis Srl) ; coordinatore: D. Roberto. Università degli Studi di Milano, 2014 Dec 05. 27. ciclo, Anno Accademico 2014. [10.13130/calogero-francesco_phd2014-12-05].

NEW SYNTHETIC PROCESSES FOR THE APIS INDUSTRIAL PRODUCTION: THE CASE OF SILODOSIN

F. Calogero
2014

Abstract

This thesis is focused on the development of new synthetic processes for the production of already known Active Pharmaceutical Ingredients (APIs). The research work was performed in the laboratories of Dipharma Francis srl, a company which operates in the generic drug market. The launch of the generic version of a drug in the market often leads to lowering of product prices for both the branded product and the generic ones. For this reason, the process adopted to produce an API has to be innovative, efficient, safe and, of course, cheaper than the existing ones, in order to be competitive in the market. During my Ph.D. I worked on the synthesis of some APIs, in particular here I report the feasibility and development studies of an alternative process to produce silodosin. Silodosin is an API used as a treatment for the symptoms of Benign Prostatic Hyperplasia (BPH). In order to establish the synthetic strategy and to outline our freedom to operate, an accurate survey of the whole patent literature about silodosin has been done. During the feasibility study several synthetic approaches have been tried in order to functionalise indoline at positions 5 and 7. A copper(I) catalysed C-arylation reaction and a regioselective electrophilic aromatic substitution revealed to be the best choices to introduce respectively substituents in position 5 and 7 of indoline. The synthesis continued with a diastereoselective reductive amination which after crystallisation yielded optically pure amine intermediate that is the key intermediate for the synthesis of silodosin and ended converting amine intermediate into Silodosin using already reported procedures. Our new process to prepare silodosin starting from commercially available and cheap indoline consists of 11 steps. The whole synthetic route has been performed in gram scale using only 4 purifications of key intermediates. Silodosin has been finally obtained in a 10% overall yield, with a purity greater than 99% measured by HPLC and an optical purity greater than 99% measured by HPLC on chiral stationary phase.
5-dic-2014
Settore CHIM/04 - Chimica Industriale
Settore CHIM/06 - Chimica Organica
API; silodosin; total synthesis; industrial chemistry; process chemistry; organic synthesis; route scouting; copper catalysis; regioselective electrophilic substitution; crystallisation;
PASSARELLA, DANIELE
ROBERTO, DOMINIQUE MARIE
Doctoral Thesis
NEW SYNTHETIC PROCESSES FOR THE APIS INDUSTRIAL PRODUCTION: THE CASE OF SILODOSIN / F. Calogero ; tutor: D. Passarella ; co-tutor: E. Attolino (Dipharma Francis Srl) ; coordinatore: D. Roberto. Università degli Studi di Milano, 2014 Dec 05. 27. ciclo, Anno Accademico 2014. [10.13130/calogero-francesco_phd2014-12-05].
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Descrizione: New processes for the APIs industrial production: the case of silodosin
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/243613
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