- Method for preparing ropinirole hydrochloride
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The invention belongs to the technical field of medicinal chemistry and organic chemistry, and particularly relates to a method for preparing ropinirole hydrochloride. A novel compound 4 is synthesized by the aid of the method and is used as a raw material for preparing the ropinirole hydrochloride. The particular method includes dissolving the compound 4 in one or a plurality of types of ethyl alcohol/methanol/ethyl acetate to obtain liquid, adding Pd/C into the ethyl alcohol/methanol/ethyl acetate, and carrying out reaction to obtain compounds 5; dissolving the compounds 5, p-toluenesulfonylchloride and pyridine in one or a plurality of types of dichloromethane/trichloromethane/1, 2-dichloroethane/pyridine, and carrying out reaction to obtain compounds 6; dissolving the compounds 6, NaIand dipropyl amine in one or a plurality of types of DMF (dimethyl formamide)/DMSO (dimethylsulfoxide)/Toluene, and carrying out reaction to obtain ropinirole; dissolving the ropinirole in 1, 4 dioxane with hydrochloric acid, and carrying out reduced-pressure compression to obtain the ropinirole hydrochloride. A proportion of the compounds 5 to the p-toluenesulfonyl chloride to the pyridine is equal to 1:1.2:1.2. A proportion of the compounds 6 to the NaI to the dipropyl amine is equal to 1:1:1.2. The novel method for preparing the ropinirole hydrochloride has the advantages that the method includes simple and convenient steps and can be practically put into production, and raw materials for the ropinirole hydrochloride are simple and are easily available.
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- Synthesis of 2-Oxindoles from Substituted Indoles by Hypervalent-Iodine Oxidation
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A practical conversion of indoles into the corresponding 2-oxindoles is achieved efficiently using a hypervalent iodine reagent. This oxidation is amenable to different substituted indoles, and allows the synthesis of a wide range of synthetically valuable substituted 2-oxindoles in up to 90 % yield. Furthermore, Ropinirole, a drug used to alleviate the symptoms of Parkinson's disease, was synthesized in three steps in an overall yield of 44 % using this method.
- Jiang, Xinpeng,Zheng, Cong,Lei, Lijun,Lin, Kai,Yu, Chuanming
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p. 1437 - 1442
(2018/04/06)
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- The development of a short route to the API ropinirole hydrochloride
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A four-step, three-stage synthesis of the API ropinirole hydrochloride has been developed from a commercially available naphthalene derivative. The new route has half the step-count and twice the overall yield of the current manufacturing process. Key features of the synthesis are a regioselective Birch reduction and an ozonolysis with concomitant ring closure to induce the required ring contraction.
- Yousuf, Zeshan,Richards, Andrew K.,Dwyer, Andrew N.,Linclau, Bruno,Harrowven, David C.
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p. 10532 - 10539
(2015/11/10)
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- Synthesis and pharmacological evaluation of dual acting ligands targeting the adenosine A2A and dopamine D2 receptors for the potential treatment of parkinsons disease
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A relatively new strategy in drug discovery is the development of dual acting ligands. These molecules are potentially able to interact at two orthosteric binding sites of a heterodimer simultaneously, possibly resulting in enhanced subtype selectivity, higher affinity, enhanced or modified physiological response, and reduced reliance on multiple drug administration regimens. In this study, we have successfully synthesized a series of classical heterobivalent ligands as well as a series of more integrated and drug-like dual acting molecules, incorporating ropinirole as a dopamine D2 receptor agonist and ZM 241385 as an adenosine A2A receptor antagonist. The best compounds of our series maintained the potency of the original pharmacophores at both receptors (adenosine A2A and dopamine D2). In addition, the integrated dual acting ligands also showed promising results in preliminary blood-brain barrier permeability tests, whereas the classical heterobivalent ligands are potentially more suited as pharmacological tools.
- J?rg, Manuela,May, Lauren T.,Mak, Frankie S.,Lee, Kiew Ching K.,Miller, Neil D.,Scammells, Peter J.,Capuano, Ben
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supporting information
p. 718 - 738
(2015/01/30)
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- Investigation of novel ropinirole analogues: Synthesis, pharmacological evaluation and computational analysis of dopamine D2 receptor functionalized congeners and homobivalent ligands
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Herein, we report the development of novel functionalized congeners of ropinirole toward the design of pharmacological tools to probe structural requirements at the dopamine D2 receptor. Subsequently, we have used the functionalized amine congener 11 and synthesized and pharmacologically evaluated a series of homobivalent ligands of ropinirole with designated spacer lengths ranging from 14 to 30 atoms. The most potent homobivalent ligands (22-, 26- and 30-atom spacers) showed approximately 20- to 80-fold greater potency (EC50 = 3.9, 6.2 and 14 nM, respectively) than ropinirole (304 nM) in a [35S]GTPγS functional assay. Molecular modeling studies suggest that the observed increase in potency of the homobivalent ligands is possibly due to a bitopic binding mode involving the orthosteric site and an allosteric interaction at the dopamine D2 receptor protomer rather than bridging interactions at two orthosteric sites across a dopamine D 2 receptor dimer. This research has the potential to advance the development of structurally related bitopic ligands, biomarkers such as radioligands and fluorescently labeled probes, and furnish new homo- and heterobivalent ligands towards a better understanding of the dopamine D 2 receptor and potential novel treatment for Parkinson's disease.
- J?rg, Manuela,Kaczor, Agnieszka A.,Mak, Frankie S.,Lee, Kiew Ching K.,Poso, Antti,Miller, Neil D.,Scammells, Peter J.,Capuano, Ben
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supporting information
p. 891 - 898
(2014/07/08)
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- 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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- Novel process for ropinirole preparation
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A method for producing compounds of the formula: Wherein R2 is selected from the group consisting of amino, lower alkylamino, di-lower alkylamino, allylamino, diallylamino, N-lower alkyl-N-allylamino, benzylamino, dibenzylamino, phenethylamino, diphenethylamino, 4-hydroxyphenethylamino or di-(4-hydroxyphenethylamino); comprising: a) reacting with Wittig Reagent to produce wherein R1 is alkoxyl; f) hydrolyzing compound II under acidic conditions to produce g) subjecting compound III to reduction and amination to produce the tertiary amine wherein R2 is as defined above; h) reacting compound IV with 4-chlorophenoxyacetonitrile to create nucleophilic substitution to produce the nitrile compound wherein R2 is as defined above; and i) effecting reduction and hydrolysis in the same step with palladium/C and sodium hydroxide to produce wherein R2 is as defined above.
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Page/Page column 4
(2009/03/07)
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- Subtantially pure ropinirole hydrochloride, polymorphic form of ropinirole and process for their preparation
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Ropinirole hydrochloride substantially free of impurities and a process for its preparation is provided. Also provided is ropinirole base substantially in polymorph Form A and a process for its preparation. Pharmaceutical compositions containing the same are also provided.
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Page/Page column 6-7
(2008/06/13)
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- SUBSTANTIALLY PURE 4-[2-(DI-N-PROPYLAMINO)ETHYL]-2(3H)-INDOLONE HYDROCHLORIDE
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Substantially pure 4-[2-(Di -n-propylamino)ethyl]-2(3h)-indolone hydrochloride having HPLC purity equal to or greater than 99.5 % and the process of its preparation.
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Page/Page column 8
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF ROPINIROLE
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A new process for the preparation of Ropinirole (1) and pharmaceutically acceptable hydrochloride salt thereof comprising reacting the compound V with nitromethane to obtain the compound of formula 11, which is reduced to compound III and alkylated to obtain compound IV. The oxidation of the indole ring provides the compound of formula (I).
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Page/Page column 6
(2008/06/13)
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- Synthesis of 4-N,N-dialkylaminoethyl-2-indolones as potential dopamine agonists
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A set of fourteen 4-ethyl>-2-indolone analogues of dopamine were synthesized in 15 steps and evaluated for their affinities towards the D2 receptor using sulpiride or spiperone as radioligands.Six analogues displayed D2 agonist activities comparable (Ki = 450 - 650 nM) to Ropinirole or SK and F 101468.The functionalized amino side chain introduced in the 4-position can be used to modulate the lipophlicity of the analogues without significantly affecting D2 activity. - Keywords: lactam; indolone; rigid dopamine analogue; D2 receptor binding
- Namil, A.,Benoit-Guyod, M.,Leclerc, G.
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p. 973 - 982
(2007/10/03)
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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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- Syntheses and in Vitro Evaluation of 4-(2-Aminoethyl)-2(3H)-indolones and Related Compounds as Peripheral Prejunctional Dopamine Receptor Agonists
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A series of (β-aminoethyl)indolones and related compounds was synthesized and evaluated in vitro as peripheral prejunctional dopaminergic agonists in the field-stimulated isolated perfused rabbit ear artery. 4--7-hydroxy-2(3H)-indolone (26) was the most potent compound (ED50 = 2 +/- 0.3 nM) tested, while the related secondary amine 24 and the des-OH derivatives 28 and 34 were only slightly less potent. 4-Methoxy-benzeneethanamine and 2-methyl-3-nitrophenylacetic acid were employed as starting materials for the synthesis of the 4-(β-aminoethyl)indolones.The ring-opened 3-acylamino analogues 46 and 47 were prepared via nitration of the phenethylamine 43 derived from 4-methoxyphenylacetic acid.The inactive isomeric indolones 38, 39, and 41 were derived from 4-nitrobenzeneethanamine and from indolone-6-acetic acid (13).
- DeMarinis, Robert M.,Gallagher, Gregory,Hall, Ralph F.,Franz, Robert G.,Webster, Charles,et al.
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p. 939 - 947
(2007/10/02)
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- 4--2(3H)-indolone: A Prejunctional Dopamine Receptor Agonist
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4--2(3H)-indolone (1c) (SK and F 101468) is a potent and selective prejunctional dopamine receptor agonist.It caused a dose-related inhibition of the constrictor response to electrical stimulation in the isolated perfused rabbit ear artery (EC50 = 100 nM), and this response was antagonized by (S)-sulpiride (KB = 7 nM).Compound 1c did not stimulate or block dopamine-sensitive adenylate cyclase and did not produce stimulation of the central nervous system in rats.It was prepared from (2-methyl-3-nitrophenyl)acetic acid in a multistep sequence based on the Reissert indole synthesis.
- Gallagher, Gregory,Lavanchy, Patricia G.,Wilson, James W.,Hieble, J. Paul,DeMarinis, Robert M.
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p. 1533 - 1536
(2007/10/02)
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