The scope of this Thesis project consists in investigating new synthetic pathways for the synthesis of trialkyl substituted benzene intermediates, useful for industrial production of API for generic drugs market. Among these molecules, a new drug, Siponimod (BAF312) known form Novartis patent US20170027907A1, is of particular interest: it was in fact recently approved by FDA for the treatment of recurrent forms of multiple sclerosis in adults. The 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one is an important intermediate for the synthesis of Siponimod and its market prospects are promising. There can be found just a few examples in the literature for its synthesis, and all of them use highly functionalized and so really expensive starting materials, on which are made few synthetic steps to obtain the desired product. All of the retrosynthetic disconnections of 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one were examined in order to simplify the target molecule structure and find cheap and commercially available starting materials which are functionalizable through known reactions. 2-ethylaniline was chosen as starting material, for its commercial availability, its cheapness (Sigma 20€/250g) and because it is synthetically smart: the amine group is as an activating one and it can be converted in a lot of functional groups through known reactions. In the chosen synthetic pathway for 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one synthesis, 2-ethylaniline was regioselectively brominated to obtain 4-bromo-2-ethylaniline, which was then protected as N-(4-bromo-2-ethylphenyl)acetamide; on this substrate was made a Sonogashira reaction to introduce an alkyne moiety to obtain N-(2-ethyl-4-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)acetamide. The acetamide was then deprotected to undergo a Sandmeyer reaction to obtain 4-(4-amino-3-ethylphenyl)-2-methylbut-3-yn-2-ol. What remains to investigate are the two last synthetic steps for the preparation of 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one, which are the Grignard reaction in presence of formaldehyde on 4-(4-amino-3-ethylphenyl)-2-methylbut-3-yn-2-ol and the deprotection and subsequent hydratation of the alkyne to obtain the target molecule. Of great synthetic interest was the positive outcome of the Buchwald reaction in presence of nitroethane on substrates which are electronically different from the ones described, like N-(4-bromophenyl)acetamide. The reaction conditions need to be optimized to improve the yield.
Lo scopo del seguente lavoro di Tesi è quello di indagare nuove metodologie sintetiche per la preparazione di intermedi benzenici trialchil sostituiti, utili alla produzione su scala industriale di composti farmaceutici (API) per il mercato generico. Tra questi composti di particolare interesse risulta un nuovo farmaco, Siponimod (BAF312) noto dal brevetto US20170027907A1 di Novartis; è stato recentemente approvato dall’ FDA per il trattamento delle forme recidivanti della sclerosi multipla negli adulti. L’1-[3-etil-4-(idrossimetil)fenil]etanone è un importante intermedio per la sintesi del Siponimod e le sue prospettive sul mercato sono promettenti. La letteratura fornisce pochi esempi per la sua sintesi, tutti accomunati dall’impiego di starting material già altamente funzionalizzati e dunque costosi, che prevedono ulteriori step sintetici per ottenere il prodotto desiderato. Sono state esaminate tutte le possibili disconnessioni retrosintetiche dell’1-[3-etil-4-(idrossimetil)fenil]etanone, al fine di semplificarne la struttura e trovare starting material economici e commercialmente disponibili da poter funzionalizzare attraverso reazioni note. Si è optato per l’utilizzo della 2-etilanilina come materiale di partenza, essendo commercialmente disponibile, economica (Sigma 20€/250g) e smart dal punto di vista sintetico; infatti, il gruppo amminico può agire da gruppo attivante e successivamente può essere interconvertito in un gran numero di gruppi funzionali attraverso reazioni note. Nella strada sintetica scelta per la sintesi dell’1-[3-etil-4-(idrossimetil)fenil]etanone, la 2-etilanilina è stata bromurata regioselettivamente a dare la 4-bromo-2-etilanilina, poi protetta come N-(4-bromo-2-etilfenil)acetamide; su questo substrato è stata poi effettuata la reazione di Sonogashira con la quale è stato introdotto un triplo legame protetto per ottenere l’N-(2-etil-4-(3-idrossi-3-metillbut-1-in-1-il)fenil)acetammide. Successivamente l’acetammide è stata deprotetta, ha subito una reazione di Sandmeyer fino ad ottenere il 4-(4-bromo-3-etilfenil)-2-metilbut-3-in-2-olo. Ciò che rimane da indagare sono gli ultimi due step previsti per la sintesi dell’1-[3-etil-4-(idrossimetil)fenil]etanone ovvero la reazione di Grignard in presenza di formaldeide sul 4-(4-bromo-3-etilfenil)-2-metilbut-3-in-2-olo e la deprotezione e conseguente idratazione dell’alchino fino ad ottenere la molecola target. Di notevole interesse sintetico è stato l’esito positivo della variante della reazione di Buchwald in presenza di nitroetano su substrati elettronicamente diversi da quelli descritti, come la N-(4-bromofenil)acetammide. Rimangono da ottimizzare le condizioni di reazione per aumentarne la resa.
Nuovi processi sintetici per la preparazione di intermedi aromatici trisostituiti di interesse farmaceutico
D'AURIA, FELISIA
2018/2019
Abstract
The scope of this Thesis project consists in investigating new synthetic pathways for the synthesis of trialkyl substituted benzene intermediates, useful for industrial production of API for generic drugs market. Among these molecules, a new drug, Siponimod (BAF312) known form Novartis patent US20170027907A1, is of particular interest: it was in fact recently approved by FDA for the treatment of recurrent forms of multiple sclerosis in adults. The 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one is an important intermediate for the synthesis of Siponimod and its market prospects are promising. There can be found just a few examples in the literature for its synthesis, and all of them use highly functionalized and so really expensive starting materials, on which are made few synthetic steps to obtain the desired product. All of the retrosynthetic disconnections of 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one were examined in order to simplify the target molecule structure and find cheap and commercially available starting materials which are functionalizable through known reactions. 2-ethylaniline was chosen as starting material, for its commercial availability, its cheapness (Sigma 20€/250g) and because it is synthetically smart: the amine group is as an activating one and it can be converted in a lot of functional groups through known reactions. In the chosen synthetic pathway for 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one synthesis, 2-ethylaniline was regioselectively brominated to obtain 4-bromo-2-ethylaniline, which was then protected as N-(4-bromo-2-ethylphenyl)acetamide; on this substrate was made a Sonogashira reaction to introduce an alkyne moiety to obtain N-(2-ethyl-4-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)acetamide. The acetamide was then deprotected to undergo a Sandmeyer reaction to obtain 4-(4-amino-3-ethylphenyl)-2-methylbut-3-yn-2-ol. What remains to investigate are the two last synthetic steps for the preparation of 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one, which are the Grignard reaction in presence of formaldehyde on 4-(4-amino-3-ethylphenyl)-2-methylbut-3-yn-2-ol and the deprotection and subsequent hydratation of the alkyne to obtain the target molecule. Of great synthetic interest was the positive outcome of the Buchwald reaction in presence of nitroethane on substrates which are electronically different from the ones described, like N-(4-bromophenyl)acetamide. The reaction conditions need to be optimized to improve the yield.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/21396