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New route to the API Ropinirole Hydrochloride and towards new synthetic applications of squaramides

New route to the API Ropinirole Hydrochloride and towards new synthetic applications of squaramides
New route to the API Ropinirole Hydrochloride and towards new synthetic applications of squaramides
This thesis describes our efforts in developing a new synthesis of the active pharmaceutical ingredient (API) ropinirole hydrochloride, used in the symptomatic treatment of Parkinson’s disease and Restless Leg Syndrome. The API in Requip™ (marketed by GlaxoSmithKline) is currently prepared in 12% overall yield using a nine-step sequence, however, several generic routes have since been established in the pharmaceutical market. Herein we describe a shorter and more efficient route to ropinirole hydrochloride that could prove attractive from an industrial perspective.
The strategies employed in developing the new synthesis of the API are presented - adopting Plieninger’s approach to 4-substituted indoles with a contemporary twist. Key transformations include the use of a dissolving metal reduction followed by an ozonolysis under flow to construct the API’s heterocyclic core. In our first approach the target is attained in six-steps from 1-aminonaphthalene. However, by increasing the oxidation level of the starting material we were able to achieve a synthesis of ropinirole hydrochloride in four steps from a commercial starting material.
Also described in this thesis are our efforts towards probing the synthetic versatility of squaramides. Preliminary results indicate that the stabilisation exhibited by their derivatives may lead to alternative thermal rearrangement pathways, complimentary to squarates.
Yousuf, Zeshan
ecff6693-0953-4bfb-9ff1-485971bb3570
Yousuf, Zeshan
ecff6693-0953-4bfb-9ff1-485971bb3570
Harrowven, David
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(2015) New route to the API Ropinirole Hydrochloride and towards new synthetic applications of squaramides. University of Southampton, Chemistry, Doctoral Thesis, 207pp.

Record type: Thesis (Doctoral)

Abstract

This thesis describes our efforts in developing a new synthesis of the active pharmaceutical ingredient (API) ropinirole hydrochloride, used in the symptomatic treatment of Parkinson’s disease and Restless Leg Syndrome. The API in Requip™ (marketed by GlaxoSmithKline) is currently prepared in 12% overall yield using a nine-step sequence, however, several generic routes have since been established in the pharmaceutical market. Herein we describe a shorter and more efficient route to ropinirole hydrochloride that could prove attractive from an industrial perspective.
The strategies employed in developing the new synthesis of the API are presented - adopting Plieninger’s approach to 4-substituted indoles with a contemporary twist. Key transformations include the use of a dissolving metal reduction followed by an ozonolysis under flow to construct the API’s heterocyclic core. In our first approach the target is attained in six-steps from 1-aminonaphthalene. However, by increasing the oxidation level of the starting material we were able to achieve a synthesis of ropinirole hydrochloride in four steps from a commercial starting material.
Also described in this thesis are our efforts towards probing the synthetic versatility of squaramides. Preliminary results indicate that the stabilisation exhibited by their derivatives may lead to alternative thermal rearrangement pathways, complimentary to squarates.

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Published date: 19 February 2015
Organisations: University of Southampton, Chemistry

Identifiers

Local EPrints ID: 374785
URI: http://eprints.soton.ac.uk/id/eprint/374785
PURE UUID: 440f10ad-05c0-4c28-ad1e-f0b24ca2d3cc
ORCID for David Harrowven: ORCID iD orcid.org/0000-0001-6730-3573

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Date deposited: 11 May 2015 10:03
Last modified: 14 Jul 2018 00:36

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