3899-07-8Relevant articles and documents
Investigation of various N-heterocyclic substituted piperazine versions of 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol: Effect on affinity and selectivity for dopamine D3 receptor
Brown, Dennis A.,Mishra, Manoj,Zhang, Suhong,Biswas, Swati,Parrington, Ingrid,Antonio, Tamara,Reith, Maarten E.A.,Dutta, Aloke K.
, p. 3923 - 3933 (2009)
Here we report on the design and synthesis of several heterocyclic analogues belonging to the 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol series of molecules. Compounds were subjected to [3H]spiperone binding assays, carried out with HEK-293 cells expressing either D2 or D3 dopamine receptors, in order to evaluate their inhibition constant (Ki) at these receptors. Results indicate that N-substitution on the piperazine ring can accommodate various substituted indole rings. The results also show that in order to maintain high affinity and selectivity for the D3 receptor the heterocyclic ring does not need to be connected directly to the piperazine ring as the majority of compounds included here are linked either via an amide or a methylene linker to the heterocyclic moiety. The enantiomers of the most potent racemic compound 10e exhibited differential activity with (-)-10e (Ki; D2 = 47.5 nM, D3 = 0.57 nM) displaying higher affinity at both D2 and D3 receptors compared to its enantiomer (+)-10e (Ki; D2 = 113 nM, D3 = 3.73 nM). Additionally, compound (-)-10e was more potent and selective for the D3 receptor compared to either 7-OH-DPAT or 5-OH-DPAT. Among the bioisosteric derivatives, the indazole derivative 10g and benzo[b]thiophene derivative 10i exhibited the highest affinity for D2 and D3 receptors. In the functional GTPγS binding study, one of the lead molecules, (-)-15, exhibited potent agonist activity at both D2 and D3 receptors with preferential affinity at D3.
Intensification of Free-Radical Racemization for a Non-activated Amine in a Continuous Flow Reactor
Toussaint, Frédéric C.,Defrance, Thierry,Decouvreur, Serge,Carly, Nicolas,Merschaert, Alain
, p. 3389 - 3396 (2020)
The free-radical racemization of non-activated amines is a powerful tool for process design in the pharmaceutical industry, allowing the recycling of undesired enantiomers after chiral separation. This paper describes the development of the free-radical racemization of a key API intermediate in a continuous flow reactor. Upon development, a significant reduction of the solvent usage and radical initiator was made possible thanks to the conversion into a continuous flow mode. This intensification positively impacted both the environmental footprint and the safety of the reaction as well as maintaining satisfactory productivity.
Synthesis of Pharmaceutically Relevant 2-Aminotetralin and 3-Aminochroman Derivatives via Enzymatic Reductive Amination
Citoler, Joan,Harawa, Vanessa,Marshall, James R.,Bevinakatti, Han,Finnigan, James D.,Charnock, Simon J.,Turner, Nicholas J.
, p. 24456 - 24460 (2021/10/19)
2-Aminotetralin and 3-aminochroman derivatives are key structural motifs present in a wide range of pharmaceutically important molecules. Herein, we report an effective biocatalytic approach towards these molecules through the enantioselective reductive coupling of 2-tetralones and 3-chromanones with a diverse range of primary amine partners. Metagenomic imine reductases (IREDs) were employed as the biocatalysts, obtaining high yields and enantiocomplementary selectivity for >15 examples at preparative scale, including the precursors to Ebalzotan, Robalzotan, Alnespirone and 5-OH-DPAT. We also present a convergent chemo-enzymatic total synthesis of the Parkinson's disease therapy Rotigotine in 63 % overall yield and 92 % ee.
Preparation method of rotigotine
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Paragraph 0064-0066, (2021/08/11)
The invention relates to the technical field of medicine preparation, and discloses a preparation method of rotigotine, which comprises the following steps: by taking 5-methoxy-2-tetralone as an initial raw material, reacting with R-alpha-methylbenzylamine, performing debenzylation reduction and S-mandelic acid chiral resolution, then reacting with a propionyl chloride reagent to generate an amide compound, and then reducing by a sodium borohydride reagent to obtain the rotigotine; and finally, reacting with 2-(thiophene-2-yl) 2-nitric acid benzene sulfonic acid ethyl ester to obtain the rotigotine. The preparation process route is as follows: the rotigotine is mild in preparation condition, simple and convenient to operate, relatively high in yield of key intermediates, high in optical purity and easy for industrial large-scale production, and has a very good application prospect.
Preparation method for rotigotine
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, (2019/04/17)
The invention discloses a preparation method for rotigotine. The preparation method includes the following steps: S1. performing an amination reduction reaction on a 5-methoxy-2-tetralone solution, tert-butanesulfinamide, a catalyst, and sodium borohydride to obtain a substance A; S2. performing an alkylation reaction on a solution of the substance A, bromopropane, and a basic catalyst to obtain asubstance B; S3. reacting the substance B with a hydrochloric acid methanol solution to obtain a substance C; S4. performing a reaction on the substance C, 2-(2-bromoethyl)thiophene, potassium carbonate, and N,N-dimethylformamide to obtain a substance D; and S5. reacting acetic acid with hydrogen bromide to obtain the rotigotine. The preparation method is simple in operation, is high in yield, ismild in reaction condition, is green and environmentally friendly, is high in purity of the prepared rotigotine, and is suitable for large-scale industrial production.
Enantioselective Synthesis of β-Aminotetralins via Chiral Phosphoric Acid-catalyzed Reductive Amination of β-Tetralones
Park, Do Young,Kim, Kyung-Hee,Cheon, Cheol-Hong
, p. 462 - 467 (2017/12/07)
A new protocol for the synthesis of chiral β-aminotetralins has been developed via chiral phosphoric acid-catalyzed asymmetric reductive amination of β-tetralones using a Hantzsch ester as an organic hydride donor. Various chiral β-aminotetralins were obtained in good yields with good to high enantioselectivities. Furthermore, the utility of our new protocol was successfully demonstrated in the enantioselective synthesis of rotigotine. (Figure presented.).
Optical Control of Dopamine Receptors Using a Photoswitchable Tethered Inverse Agonist
Donthamsetti, Prashant C.,Winter, Nils,Sch?nberger, Matthias,Levitz, Joshua,Stanley, Cherise,Javitch, Jonathan A.,Isacoff, Ehud Y.,Trauner, Dirk
, p. 18522 - 18535 (2018/01/08)
Family A G protein-coupled receptors (GPCRs) control diverse biological processes and are of great clinical relevance. Their archetype rhodopsin becomes naturally light sensitive by binding covalently to the photoswitchable tethered ligand (PTL) retinal. Other GPCRs, however, neither bind covalently to ligands nor are light sensitive. We sought to impart the logic of rhodopsin to light-insensitive Family A GPCRs in order to enable their remote control in a receptor-specific, cell-type-specific, and spatiotemporally precise manner. Dopamine receptors (DARs) are of particular interest for their roles in motor coordination, appetitive, and aversive behavior, as well as neuropsychiatric disorders such as Parkinson's disease, schizophrenia, mood disorders, and addiction. Using an azobenzene derivative of the well-known DAR ligand 2-(N-phenethyl-N-propyl)amino-5-hydroxytetralin (PPHT), we were able to rapidly, reversibly, and selectively block dopamine D1 and D2 receptors (D1R and D2R) when the PTL was conjugated to an engineered cysteine near the dopamine binding site. Depending on the site of tethering, the ligand behaved as either a photoswitchable tethered neutral antagonist or inverse agonist. Our results indicate that DARs can be chemically engineered for selective remote control by light and provide a template for precision control of Family A GPCRs.
luo Ti gastrodia tuber of a kind of preparation method
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Paragraph 0021; 0036; 0038, (2017/02/24)
The invention discloses a preparation method of rotigotine, and belongs to the technical field of medicine synthesis. According to the method, 5-methoxy-2-tetralone is used as a raw material for amination, asymmetric reduction, halogenation and methoxyl group removal four step reaction for synthesis of chiral rotigotine {(-)-(S)-2-(N-propyl-N-(2-(2-thiophene) ethyl] amino]-5-hydroxy-1, 2, 3, 4-tetralin}. According to the method, a simplex stereoscopic structural compound is synthesized by stereo selective chemical reaction, in the asymmetric reduction process, hantzsch ester 1, 4-dihydropyridine (HEH) is used as a reducing agent, and chiral phosphoric acid is used as a catalyst to synthesize an important intermediate (S)-2-(N-n-propyl) amido-5-methoxy tetralin (II) with a simplex stereoscopic structure, the use of a chiral reagent for splitting to obtain the simplex stereoscopic structural compound is avoided, the synthesis procedure is shortened, the yield is improveds, and the method is favorable for industrialized production.
PROCESSES FOR THE PREPARATION OF ROTIGOTINE AND INTERMEDIATES THEREOF
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Page/Page column 43, (2016/04/20)
The present invention provides processes for the preparation of a compound of Formula 2 or a salt thereof, wherein R1 is selected from the group consisting of H, C1-C3 alkyl, and C(0)R3; R3 is selected from the group consisting of C1-C6 alkyl, C6-C10aryl and C7-C20 arylalkyl; the carbon atom marked with "*" is racemic, enantiomerically enriched in the (R)-configuration, or enantiomerically enriched in the (S)-configuration. Also provided are intermediate compounds of the processes.
New catalytic route for the synthesis of an optically active tetralone-derived amine for rotigotine
Cobley, Christopher J.,Evans, George,Fanjul, Tamara,Simmonds, Shaun,Woods, Amy
supporting information, p. 986 - 989 (2016/02/18)
Rotigotine is a launched drug for the treatment of Parkinson's disease and restless legs syndrome. The key steps of an alternative route for the synthesis of rotigotine have been demonstrated. Formation of a prochiral enamide, asymmetric hydrogenation of the enamide with high enantioselectivity, and reduction of the resulting amide to an amine have been proved to work successfully. The best conditions screened to date for the asymmetric hydrogenation of enamide 9 to amide 10 were with [(RuCl((R)-T-BINAP))2(μ-Cl)3][NH2Me2] at 25 bar H2 and 30 °C (500:1 S/C ratio, 99% conversion, 91% ee S). Reduction of amide 10 to amine 5 was best achieved with Red-Al giving 95% conversion.
