- A convenient synthesis of 4-(2-hydroxyethyl)indolin-2-one, a useful intermediate for the preparation of both dopamine receptor agonists and protein kinase inhibitors
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This paper describes a practical approach to the preparation of 4-(2-hydroxyethyl)indolin-2-one, a key intermediate in the synthesis of dopaminergic agonists such as ropinirole - a drug used in the treatment of Parkinson's disease and restless legs syndrome - and of two sets of protein kinase inhibitors. The sequence starts from commercially available 2-(2-methyl-3-nitrophenyl)acetic acid, which is converted in five steps into the desired target compound. This procedure offers a convenient alternative route to existing methodologies, given its milder reaction conditions, ease of implementation, and its overall yield (59 %).
- Matera, Carlo,Quadri, Marta,Pelucchi, Silvia,De Amici, Marco,Dallanoce, Clelia
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p. 1139 - 1144
(2014/06/24)
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- Development of large-scale syntheses of ropinirole in the pursuit of a manufacturing process
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Two plant syntheses of ropinirole {4-[2-(di-n-propyIamino)-ethyl]-1,3-dihydro-2H-indolin-2-one hydrochloride, SK&F-101468-A} using the ferric chloride mediated cyclisation of β-nitrostyrenes to form 3-chlorooxindoles as the key step are described. The first synthesis suffered the severe limitation of the final-step chemistry being nonselective in the reaction between di-n-propylamine and the bromide precursor to ropinirole as both substitution and elimination pathways were promoted and by-product formation at a level of 40% resulted. This problem was rectified in the latter synthesis by the more selective reaction between di-n-propylamine and the sulfonate ester precursor promoting ropinirole formation to a level of 88%. This second synthesis is now used as the commercial route, and problems (and their solutions) identified during the development of this route are now described. The identification of novel by-products which enabled the Sommelet oxidation step to be optimised is also reported. A unimolecular decomposition mechanism during hydrolysis of the hexaminium salt to form the key benzaldehyde intermediate is proposed and substantiated with experimental data.
- Hayler, John D.,Howie, Simon L. B.,Giles, Robert G.,Negus, Alan,Oxley, Paul W.,Walsgrove, Timothy C.,Whiter
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- Some synthetic approaches to ropinirole (SK and F 101468-A): A potent dopamine receptor agonist
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Three new routes to ropinirole (SK and F 101468-A, 1) are described each involving the preparation of 3-chlorooxindole intermediates of type 3 from β-nitrostyrenes as the pivotal step. The superiority of sulphonate esters 17a-c as direct precursors to 1 over the bromide 11 is also described.
- Hayler,Howie,Giles,Negus,Oxley,Walsgrove,Walsh,Dagger,Fortunak,Mastrocola
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p. 875 - 882
(2007/10/02)
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