magistrsko delo
Darja Prudič (Author), Peter Krajnc (Mentor)

Abstract

(R)-1-aminoindan je pomemben intermediat za sintezo zdravilne farmacevtske učinkovine rasagilina, (R)(+)-N-propargil-1-aminoindana, oz. njegove soli. Zdravila osnovana na navedeni učinkovini se uporabljajo za zdravljenje indikacij Parkinsonove bolezni, motenj spomina, demence tipa Alzheimerjeve bolezni, depresije in hiperaktivnega sindroma pri otrocih. Magistrska naloga temelji na razvoju učinkovite sinteze (R)-1-aminoindana in preveritvi ter potrditvi ustreznosti tega ključnega intermediata za nadaljnjo sintezo (R)(+)-N-propargil-1-aminoindana. Eksperimentalno delo smo razporedili v tri sklope. V prvem smo zajeli razvoj in optimizacijo sinteze racemnega 1-aminoindana, osnovane na postopku reduktivnega aminiranja 1-indanona z amonijakom v prisotnosti kombinacije reagenta Ti(OiPr)4–NaBH4. V drugem sklopu smo opisali razvoj in optimizacijo resolucije racemnega 1-aminoindana v (R)-1-aminoindan ter razklop nastale soli z nevtralizacijo do proste baze (R)-1-aminoindana. Tekom raziskav smo izvedli preveritev možnosti uporabe različnih kiralnih kislinskih reagentov za tvorbo diastereoizomerne soli. Izkazalo se je, da je najučinkovitejša izvedba z N-acetil-L-glutaminsko kislino. Diastereoizomerno resolucijo smo izvedli v treh korakih. Najprej smo neselektivno tvorili sol v kristalizacijskem mediju etanol/terc butil metil eter (EtOH/TBME), nato selektivno rekristalizirali tvorjeno sol v etanolu do (R)-1-aminoindana (HPLC enantiomerni presežek > 70 %) ter sol ponovno rekristalizirali v sistemu EtOH/voda in tako pripravili (R)-1-aminoindan z zastavljenim enantiomernim presežkom > 98 %. V tretjem sklopu smo potrdili ustreznost pripravljenega intermediata (R)-1-aminoindana za sintezo zdravilne farmacevtske učinkovine (R)(+)-N-propargil-1-aminoindan, na osnovi reakcije nukleofilne substitucije s proparagil benzen sulfonatom v prisotnosti vodne raztopine natrijevega hidroksida (NaOH) v toluenu.

Keywords

(R)-1-aminoindan;reduktivno aminiranje;N-acetil-L-glutaminska kislina;diastereoizomerna resolucija;(R)(+)-N-propargil-1-aminoindan;

Data

Language: Slovenian
Year of publishing:
Typology: 2.09 - Master's Thesis
Organization: UM FKKT - Faculty of Chemistry and Chemical Engineering
Publisher: [D. Prudič]
UDC: 546:615.45(043.2)
COBISS: 18234902 Link will open in a new window
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Other data

Secondary language: English
Secondary title: SYNTHESIS OF ( R )-1-AMINOINDANE
Secondary abstract: (R)-1-aminoindane has been applied as an intermediate for the synthesis of active pharmaceutical ingredient (API) rasagiline, (R)(+)-N-propargyl-1-aminoindane or its salt. Medicines based on this API have been used for the treatment of Parkinson’s disease, memory disorders, memory disorders related to Alzheimer disease, depression and hyperactive syndromes with children. This work is focused on the development of efficient synthesis route for the preparation of optically-pure (R)-1-aminoindane. Furthermore, the prepared intermediate quality was confirmed with the use-test for the preparation of final API. The experimental work described in this work consists of three parts. In the first part the developed and optimized synthesis of 1-aminoindane, based on the procedure of reductive amination of 1-indanone using ammonia in the presence of combined reagent Ti(OiPr)4–NaBH4, is described. In the second part the developed and optimized resolution of racemic 1-aminoindane into (R)-1-aminoindane using N-acetyl-L-glutamic acid, followed by neutralization and formation of free base form of (R)-1-aminoindane, is discussed. The diastereoisomeric resolution was carried out in three consecutive steps; non-selective salt formation (reagarding the enantiomeric purity) and crystallization from medium EtOH/TBME; firstly selective re-crystallization of diastereoisomeric salt in EtOH (HPLC enantiomeric excess > 70 % of (R)-isomer), secondly selective re-crystallization of diastereoisomeric salt in EtOH/water (HPLC enantiomeric excess > 98 % of (R)-isomer) and neutralization of the purified salt for formation of optically-pure product (R)-1-aminoindane. Finally, in the third part of experimental work the quality of the prepared intermediate (R)-1-aminoindane with synthesis of API (R)(+)-N-propargyl-1-aminoindane, with the reaction of nucleophilic substitution between propargylbenzene sulphonate and prepared intermediate, is pointed out. The reaction was carried out in the presence of water solution of NaOH in reaction medium toluene.
Secondary keywords: (R)-1-aminoindane;reductive amination;N-acetyl-L-glutamic acid;distereoisomeric resolution;(R)-(+)-N-propargyl-1-aminoindane;
URN: URN:SI:UM:
Type (COBISS): Master's thesis/paper
Thesis comment: Univ. v Mariboru, Fak. za kemijo in kemijsko tehnologijo
Pages: XII, 61 f.
ID: 8729890